Trustees Of Tufts College

TUFTS CLINICAL AND TRANSLATIONAL SCIENCE INSTITUTE

TUFTS CLINICAL AND TRANSLATIONAL SCIENCE INSTITUTE (CLINICAL TRIAL DESIGN LABS SUPPLEMENT) - PROJECT SUMMARY TUFTS CLINICAL TRIAL DESIGN LABS ARE STRUCTURED MULTI-STAKEHOLDER EVENTS THAT SUPPORT DEVELOPMENT OF INNOVATIVE SOLUTIONS TO IMPROVE THE DESIGN AND IMPACT OF CLINICAL TRIALS. DURING THE FIRST YEAR OF OUR UM1 CLINICAL AND TRANSLATIONAL SCIENCE AWARD THAT STARTS MAY 1, 2023, WE WILL HOST TWO DESIGN LABS AND DEVELOP A PLAYBOOK OF MATERIALS AND TRAINING TO SUPPORT THE DISSEMINATION OF THIS APPROACH. AS WITH PRIOR DESIGN LABS LED BY THE TUFTS PART OF THE JOHNS HOPKINS-TUFTS TRIAL INNOVATION CENTER (JHU-TUFTS TIC), THE DESIGN LABS TO BE DONE UNDER THIS SUPPLEMENT WILL BE CASE-BASED AND FOCUSED ON DEVELOPMENT OF INNOVATIVE METHODOLOGY TO IMPROVE THE DESIGN AND IMPLEMENTATION OF CLINICAL TRIALS. WE WILL WORK WITH THE TRIAL INNOVATION NETWORK (TIN) TO PUT OUT A CALL FOR PROPOSALS, AND THE CLINICAL TRIAL PROPOSALS WILL BE SCORED AND CAREFULLY SELECTED BY THE DESIGN LAB TEAM. THE USE CASES THAT ARE SUCCESSFUL WILL BE THOSE WHOSE CONSIDERATION WILL ALSO PROVIDE GENERALIZABLE INFORMATION ABOUT INNOVATIVE CLINICAL TRIAL DESIGNS. THE DESIGN LAB PROCESS BEGINS WITH A SERIES OF DETAILED AND INTERACTIVE MEETINGS THAT: HELP INVESTIGATOR TEAMS CONSIDER THE RELEVANT STAKEHOLDERS FOR THEIR PROPOSED TRIAL; ENSURE THAT THEY THINK INNOVATIVELY ABOUT THE DESIGN OPTIONS AND OPPORTUNITIES; AND HONE THE QUESTIONS THAT THEY WANT TO BRING TO THE DESIGN LAB EVENT. THE PROCESS CULMINATES WITH AN EVENT THAT BRINGS TOGETHER A DIVERSE GROUP OF STAKEHOLDERS FROM ACROSS THE BIOMEDICAL SPECTRUM AND TAKES A SYSTEMS-LEVEL APPROACH TO THE PROPOSAL, FOCUSING ON HEALTH IMPACT. A REPORT IS PRODUCED AFTER THE EVENT TO SUMMARIZE THEMES AND LEARNINGS FROM THE DAY FOR THE STUDY TEAM. IN ADDITION TO THE TRIAL SPECIFIC REPORT, WHICH WILL BE CONFIDENTIAL, THE TUFTS DESIGN LAB TEAM WILL WORK WITH THE INVESTIGATOR TEAM AND THE TIN TO DISSEMINATE BROADER, GENERALIZABLE LEARNINGS ABOUT INNOVATIVE DESIGN METHODOLOGY. THE DESIGN LAB PROGRAM OF WORK WILL CONTINUE TO EVOLVE WITH INPUT AND SUPPORT FROM THE TIN, TARGETING CLINICAL TRIAL ROADBLOCKS IN INNOVATIVE WAYS, AND LEARNING FROM CASE-BASED EXAMPLES THAT BRING TOGETHER RELEVANT STAKEHOLDERS TO DISCUSS HOW TO MAKE SCIENTIFIC PROGRESS ACROSS THE TRANSLATIONAL SPECTRUM.

GOAL: TO ENHANCE THE CAPACITY OF LOCAL, NATIONAL AND REGIONAL INSTITUTIONS TO UNDERSTAND THE SPILLOVER ECOSYSTEM (SE) AND TO USE EXISTING AND NEW EVIDENCE TO ADVANCE, DEPLOY, AND ASSESS INTERVENTIONS TO REDUCE THE SPILLOVER OF EMERGING ZOONOTIC VIRUSES AT HIGH-RISK ANIMAL-HUMAN INTERFACES WHILE REDUCING AMPLIFICATION AND SPREAD.

NUTRITION COLLABORATIVE RESEARCH SUPPORT PROGRAM - FOCUS ON AFRICA

TUFTS CLINICAL AND TRANSLATIONAL RESEARCH INSTITUTE

THE PURPOSE OF THIS COLLABORATIVE EFFORT IS TO BRING TOGETHER A MULTIDISCIPLINARY GROUP OF SCIENTISTS TO ADVANCE THE STATE OF THE ART IN MEASURING, PREDICTING AND ENHANCING COGNITIVE CAPABILITIES AND HUMAN-SYSTEM INTERACTIONS FOR BOTH INDIVIDUALS AND TEAMS WORKING IN COMPLEX ENVIRONMENTS.

TUFTS CLINICAL AND TRANSLATION SCIENCE INSTITUTE (UL1)

FEED THE FUTURE FOOD SYSTEMS FOR NUTRITION INNOVATION LAB

TISSUE ENGINEERING RESOURCE CENTER

PINEO_INSTITUTIONAL_CARES_2020

CLINICAL CENTER FOR NIH'S NUTRITION FOR PRECISION HEALTH: THE ALL OF US NEW ENGLAND RESEARCH COLLABORATIVE - PROJECT SUMMARY THE ALL OF US NEW ENGLAND CLINICAL CENTER (AOU-NE-CC) IS A COLLABORATION OF NEW ENGLAND–BASED RESEARCH TEAMS WITH THE NECESSARY EXPERTISE AND RESOURCES IN NUTRITION AND CLINICAL TRANSLATIONAL SCIENCE TO IMPLEMENT SUCCESSFULLY ALL 3 MODULES OF THE NIH COMMON FUND’S NUTRITION FOR PRECISION HEALTH (NPH) CLINICAL CENTER PROGRAM. THE JEAN MAYER USDA HUMAN NUTRITION RESEARCH CENTER ON AGING AT TUFTS UNIVERSITY (TUFTS- HNRCA) AND MASSACHUSETTS GENERAL HOSPITAL (MGH) WILL LEAD THE AOU-NE-CC AND PARTNER WITH ALL OF US NEW ENGLAND TO ENSURE THE DIVERSITY OF PARTICIPANTS AND SCIENTIFIC RIGOR REQUIRED TO IDENTIFY INTER-INDIVIDUAL VARIABILITY OF RESPONSE TO DIETARY PATTERNS. THE AOU-NE-CC IS COMMITTED TO ALL OF US CORE VALUES AND HAS IMPLEMENTED BEST PRACTICES OF TEAM SCIENCE THROUGHOUT ITS DEVELOPMENT. THE AOU-NE-CC WILL SERVE AS A KEY PARTNER IN THE DEVELOPMENT OF A RIGOROUS NPH COMMON PROTOCOL AND EXAMINE HABITUAL DIETARY INTAKE (MODULE 1), MEASURE PHYSIOLOGICAL RESPONSES TO A MIXED-MEAL CHALLENGE (MODULES 1-3), AND IDENTIFY RESPONSES TO 3 INTERVENTION DIETS IN BOTH FREE-LIVING (MODULE 2) AND DOMICILED (MODULE 3) CONTROLLED FEEDING CONDITIONS. COUPLED WITH STANDARD ALL OF US DATA, THE PHYSIOLOGICAL RESPONSES COLLECTED THROUGH THESE MODULES WILL BE USED TO DEVELOP PREDICTIVE ALGORITHMS THAT INFORM PRECISION NUTRITION APPROACHES FOR LONG-TERM HEALTH. TO ATTAIN MAXIMUM METABOLIC AND MICROBIOME RESPONSE VARIABILITY, WE PROPOSE THE FOLLOWING 14-DAY ISOCALORIC DIETS FOR MODULES 2 AND 3, SEPARATED BY 4-WEEK WASHOUT PERIODS: (1) A HIGH-ADHERENCE DIETARY APPROACHES TO STOP HYPERTENSION (DASH) DIET; (2) A LOW-ADHERENCE DASH DIET; AND (3) A KETOGENIC DIET. WE ALSO PROPOSE THE USE OF THE THOROUGHLY TESTED MIXED-MEAL CHALLENGE PHENFLEX, WHICH CAN BE STANDARDIZED ACROSS CLINICAL CENTERS TO PROVIDE A MULTISYSTEM ASSESSMENT OF METABOLIC FLEXIBILITY. WITH ITS OUTSTANDING CORE FACILITIES, INCLUDING METABOLIC KITCHENS AND DOMICILED FEEDING AND NURSING CENTERS, AS WELL AS A RICH LEGACY OF CONDUCTING RIGOROUS FEEDING STUDIES, THE AOU-NE-CC IS UNIQUELY SKILLED AND POSITIONED TO SERVE AS A CLINICAL CENTER FOR THE NPH. ADDITIONAL STRENGTHS OF THE AOU-NE-CC INCLUDE EXTENSIVE EXPERIENCE IN RECRUITING CLINICAL POPULATIONS AND BIOBANKING, ENGAGING VOLUNTEERS THROUGH COMMUNITY OUTREACH, ACTIVE PARTICIPATION IN GLOBAL PRECISION NUTRITION INITIATIVES, AND AN OUTSTANDING TRACK RECORD OF PRODUCTIVE MULTISITE COLLABORATIONS IN NUTRITION, OMICS, AND PRECISION HEALTH. IMPORTANTLY, THE TUFTS-HNRCA AND MGH TEAMS ARE CLOSELY ALIGNED WITH THE ALL OF US NEW ENGLAND TEAM AND ITS RECORD OF HIGH PARTICIPANT RECRUITMENT AND RETENTION AND ITS DIVERSE COHORT, WHICH WILL SUPPORT THE NPH CONSORTIUM GOALS. BY PARTNERING WITH NPH AND ALL OF US IN THIS NOVEL MODULAR DISCOVERY SCIENCE STUDY, THE AOU-NE-CC AND ITS EXPERIENCED, FORWARD-THINKING, HIGHLY COLLABORATIVE TEAM WILL CONTRIBUTE TO THE DEVELOPMENT OF PRECISION NUTRITION APPROACHES THAT SUPPORT OPTIMAL HEALTH ACROSS THE ADULT LIFESPAN.

REILLY_CARES_2020

** AWARDS ISSUED PRIOR TO JANUARY 20, 2025, WERE FUNDED UNDER PREVIOUS ADMINISTRATIONS AND MAY NOT REFLECT THE PRIORITIES AND POLICIES OF THE CURRENT ADMINISTRATION.** AS THE WORLD POPULATION INCREASES TO 10 BILLION BY 2050, TOTAL FOOD AND MEAT PRODUCTION MUST RISE BY 70 AND 100%, RESPECTIVELY, TO SATISFY GLOBAL DEMAND. THE US FOOD PRODUCTION SYSTEM FACES SEVERAL ISSUES IN MEETING THIS DEMAND DUE TO LIMITED AVAILABLE AGRICULTURAL WATER AND LAND AND INCREASED GREENHOUSE GAS EMISSIONS. INCREASING WATER SCARCITY IN MAJOR PRODUCTION REGIONS AND INCREASING VULNERABILITY TO DISRUPTIONS FROM NATURAL DISASTERS DUE TO CLIMATE CHANGE ARE JUST SOME OF THE GROWING ISSUES THAT PROMPT THE NEED FOR NEW TECHNOLOGIES IN MEAT PRODUCTION. ALSO, A CRITICAL CHALLENGE IN FOOD SUPPLY CHAINS IS FOOD LOSS ISSUES THAT PRESENT SIGNIFICANT SUSTAINABILITY AND SECURITY CHALLENGES, WITH 60 PERCENT OF MEAT BECOMING PROCESSING WASTE (1.4 BILLION TONS FOR LIVESTOCK; 800 MILLION TONS FOR SEAFOOD). NEW SOURCES OF SUSTAINABLE PROTEIN WOULD HELP ALLEVIATE THESE CONCERNS AND ARE THE FOCUS OF THE PRESENT PROPOSAL. CULTIVATED MEAT PRODUCTION IS EMERGING AS A FEASIBLE SOLUTION TO ADDRESS IMMEDIATE SOCIETAL PROBLEMS BY DEVELOPING NEW SUSTAINABLE AGRI-FOOD SYSTEMS TO FEED A RAPIDLY GROWING GLOBAL POPULATION. THIS INDUSTRY WILL PROVIDE NUTRITIOUS AND SAFE FOODS WHILE REDUCING ENVIRONMENTAL IMPACT AND RESOURCE USAGE (78-96% FEWER GREENHOUSE GAS EMISSIONS, 99% LESS LAND USE, AND 82-96% LESS WATER USE). THIS PROJECT AIMS TO INNOVATE THE FOOD SUPPLY CHAIN FROM CELL TO FORK AND ENHANCE FOOD SUSTAINABILITY, NUTRITION, AND FOOD SECURITY BY DEVELOPING A CELL-BASED MEAT PLATFORM BASED ON THE INTEGRATION OF PHYSICAL, BIOLOGICAL, AND SOCIAL SCIENCES. CULTIVATED-MEAT PRODUCTION IS EMERGING AS AN ALTERNATIVE SOURCE OF SUSTAINABLE PROTEIN TO HELP ADDRESS NUTRITION AND FOOD SAFETY FOR CONSUMER CHOICES. THE DEVELOPMENT OF CULTIVATED-MEAT FACES MANY OBSTACLES ON AN INDUSTRIAL SCALE: (A) QUESTIONS RELATED TO CONSUMER ACCEPTANCE, PERCEPTIONS AND EXPECTATIONS; (B) TECHNICAL SOUND LIFE CYCLE AND TECHNO-ECONOMIC ANALYSES; (C) LIMITED ACCESS TO LOW-COST MEDIA AND SUITABLE CELL LINES IMPACTING SCALABILITY; (B) LACK OF AVAILABLE SUSTAINABLE BIOMATERIALS TO ACHIEVE NUTRITIOUS, SAFE, AND ORGANOLEPTICALLY ACCURATE CULTIVATED-MEAT; (C) LACK OF SYSTEMATIC APPROACHES FOR TRAINING THE NEXT GENERATION OF PROFESSIONALS. OUR CENTRAL HYPOTHESIS IS THAT A SUSTAINABLE, COST-EFFECTIVE, AND SCALABLE CULTIVATED-MEAT PLATFORM WILL INCREASE FOOD AVAILABILITY OPTIONS FOR CONSUMERS, WHILE DECREASING ENVIRONMENTAL IMPACT. THIS PROPOSED WORK AIMS TO DEVELOP NEW ADOPTABLE TECHNO-ECONOMICALLY VIABLE CULTIVATED-MEAT SYSTEMS AND DEVELOP NEW EDUCATIONAL PLATFORMS FOR TRAINING FUTURE PROFESSIONALS THROUGH SPECIFIC AIMS: 1. EVALUATE CONSUMER ACCEPTANCE AND CONSUMER WILLINGNESS-TO-PAY FOR CULTIVATED MEATS, AS WELL AS FLAVOR PROFILES; 2. ANALYZE THE ENVIRONMENTAL PERFORMANCE OF CULTIVATED MEAT PRODUCTS IN THE US; 3. OUTREACH, EXTENSION, AND EDUCATING THE NEXT GENERATION OF PROFESSIONALS FOR WORKFORCE DEVELOPMENT; 4. DEVELOP A SUSTAINABLE PLURIPOTENT STEM-CELL LINE PLATFORM; 5. DEVELOP ECONOMICALLY VIABLE SERUM-FREE MEDIA; 6. DEVELOP SUSTAINABLE BIOMATERIALS SCAFFOLDS, AND TISSUE ENGINEERING STRATEGIES, TO SUPPORT MEAT QUALITY; 7. OPTIMIZE THE PROCESSES AND BIOMATERIALS INTEGRATION TO ENHANCE NUTRITIONAL VALUE, QUALITY, AND SAFETY.

THE POINCARE INSTITUTE: A PARTNERSHIP FOR MATHEMATICS EDUCATION

RESOURCES AND WORKFORCE DEVELOPMENT FOR THE NEW ENGLAND REGIONAL BIOSAFETY LABORATORY - PROJECT SUMMARY - OVERALL THE NEW ENGLAND REGIONAL BIOSAFETY LABORATORY (NERBL) WAS ESTABLISHED IN 2008 WITH THE GOAL OF ENSURING THAT RESEARCH AND TASKS IN RESPONSE TO PATHOGENS OF PANDEMIC POTENTIAL AND OTHER EMERGING INFECTIONS (PPP/EI) ARE SAFELY, EFFICIENTLY, AND RIGOROUSLY ACCOMPLISHED. THE NERBL WAS ALSO DESIGNED TO SERVE AS A REGIONAL RESOURCE FOR ACADEMIC AND INDUSTRY PARTNERS ENGAGED IN ACTIVITIES THAT YIELD KNOWLEDGE AND MEDICAL COUNTERMEASURES TO PPP/EI AND READY TO SERVE AS DIRECTED BY NIH/NIAID/FEDERAL PARTNERS IN WHATEVER CAPACITY NECESSARY FOR PANDEMIC RESPONSE. A CRITICAL ELEMENT NECESSARY FOR EFFECTIVE FUNCTIONING OF ANY BIOSAFETY/BIOCONTAINMENT LABORATORY IS THE EXISTENCE OF CORE COMPETENCIES ASSOCIATED WITH PHYSICAL, OPERATIONAL, REGULATORY AND RESEARCH (VIVARIUM/LABORATORY) TASKS FREQUENTLY PERFORMED IN THIS SETTING. INDIVIDUALS WORKING IN THE CONTEXT OF BIOCONTAINMENT MUST POSSESS ADVANCED TECHNICAL SKILLS, HAVE UNDERGONE EXTENSIVE BSL-3/ABSL-3 TRAINING, AND CONTINUOUSLY ENHANCE THEIR KNOWLEDGE REGARDING AGENT SPECIFIC RISK. ADDITIONALLY, TO MAINTAIN OPERATIONAL INTEGRITY OF A BIOCONTAINMENT FACILITY AND ADEQUATELY SAFEGUARD THE STAFF, ENVIRONMENT, AND LOCAL COMMUNITY, FUNCTIONAL REDUNDANCIES IN THESE SKILLS AND ASSOCIATED RESPONSIBILITIES ARE AN ABSOLUTE NECESSITY. AS SUCH, THE PRIMARY OBJECTIVE OF THIS APPLICATION IS TO EXPAND AND MAINTAIN A FOOTPRINT OF HIGHLY QUALIFIED STAFF WITHIN THE NERBL THAT POSSESS A SET OF CORE COMPETENCIES FOR SPECIFIC FUNCTION CATEGORIES (I.E., VIVARIUM, FACILITIES), WHILE ALSO CROSS-TRAINED TO UNDERTAKE ADDITIONAL RESPONSIBILITIES SHOULD THE NEED ARISE. ACCORDINGLY, WE HAVE PROPOSED THREE CORES WITHIN THE CONTEXT OF THIS APPLICATION TO ACHIEVE THIS OVERARCHING GOAL. CORE 1 WILL OVERSEE FACILITY MANAGEMENT, MAINTENANCE AND OPERATIONS, ENSURING INTEGRITY AND SUSTAINABILITY OF THE NERBL INFRASTRUCTURE. CORE 2 WILL ENTAIL ACTIVITIES THAT COVER BSL3/ABSL3 BEST PRACTICES, INCLUDING LABORATORY SPECIFIC BIOSAFETY, BIOSECURITY EDUCATION, VIVARIUM SPECIFIC TRAININGS AND RESEARCH COMPETENCIES. LASTLY, CORE 3 WILL SERVE AS THE BIOCONTAINMENT RESEARCH SUPPORT SERVICES CORE, EXPANDING CAPACITIES FOR BACTERIOLOGY, VIROLOGY AND VECTOR BIOLOGY. CORE MEMBERS WILL UNDERGO RIGOROUS CROSS-TRAINING TO CREATE THE FUNCTIONAL REDUNDANCIES NECESSARY FOR ENSURING CONTINUITY OF SERVICES. TOGETHER, THESE ACTIVITIES WILL ALLOW US TO FULFILL OUR MISSION AS A RESOURCE FOR TUFTS UNIVERSITY, ACADEMIC PARTNERS, INDUSTRY ENTITIES, STATE/FEDERAL INVESTIGATORS, AS WELL AS FOR OUR RBL/NBL NETWORK MEMBERS. IMPORTANTLY, FOLLOWING COMPLETION OF THE STATED MILESTONES, THE NERBL WILL BE WELL-POSITIONED AND SUFFICIENTLY RESOURCED TO RAPIDLY RESPOND TO FUTURE EMERGING INFECTIOUS DISEASE THREATS.

TMAO AND INITIATION, EXTENT, AND CLINICAL ONSET OF ATHEROSCLEROTIC CVD

CENTER FOR ENTERIC DISEASES IN ENGINEERED TISSUES

JOINT EFFORT FOR APPLIED BRAIN AND COGNITIVE SCIENCES (ABCS)

A PROSPECTIVE STUDY OF PERSISTENT SYMPTOMS OF LYME DISEASE - ABSTRACT: OVERALL DESPITE YEARS OF RESEARCH, THERE IS NO DIAGNOSTIC TEST FOR POST-TREATMENT LYME DISEASE SYNDROME (PTLDS); THERE IS NO CONSENSUS TREATMENT FOR PTLDS; THERE IS NO AGREEMENT ON THE MECHANISMS CAUSING DISEASE OR EVEN HOW FREQUENTLY IT HAPPENS. AND WHILE THERE HAVE BEEN INTRIGUING FINDINGS BY MANY OUTSTANDING RESEARCHERS, THEY HAVE NOT BEEN INDEPENDENTLY CONFIRMED AND HAVE MOSTLY BEEN DONE IN SMALL POPULATIONS THAT HAVE IDENTIFIED PTLDS PATIENTS RETROSPECTIVELY WITHOUT SERIAL FOLLOW UP AFTER THE DIAGNOSIS OF ACUTE LYME DISEASE. IT IS HIGHLY UNLIKELY THAT THERE WILL BE A BREAKTHROUGH IN UNDERSTANDING THE DISEASE WITHOUT A MAJOR CHANGE IN THE WAY WE APPROACH STUDYING THE DISEASE. WE HYPOTHESIZE THAT ONE OF THE REASONS WHY PTLDS HAS BEEN SO INTRACTABLE TO UNDERSTAND IS THAT THE CAUSES ARE MULTIFACTORIAL AND INVOLVE A CONFLUENCE OF EVENTS INCLUDING PRIOR/CONCURRENT EXPOSURES, IMMUNOLOGICAL RESPONSES AND SPECIFIC BACTERIAL CHARACTERISTICS. IN THIS CASE, RESEARCHERS EXAMINING ONLY ONE POTENTIAL ASPECT OF THE DISEASE ARE UNLIKELY TO UNCOVER THE FULL COMPLEXITY OF THE ORIGINS OF DISEASE. WE ARE PROPOSING A PROSPECTIVE STUDY OF PTLDS, ENROLLING AND FOLLOWING SUBJECTS FROM THE TIME THEY ARE DIAGNOSED WITH ACUTE LYME DISEASE UNTIL THEY RECOVER OR DEVELOP PTLDS. WE HAVE ASSEMBLED A UNIQUE TEAM OF CLINICIANS, EPIDEMIOLOGISTS, IMMUNOLOGISTS, MICROBIOLOGISTS AND STATISTICIANS WITH A DEEP UNDERSTANDING OF LYME DISEASE AND A HISTORY OF COLLABORATION TO TACKLE THE UNDERSTANDING OF PTLDS TOGETHER. SUBJECTS WILL UNDERGO A BATTERY OF TESTS, TAKING ADVANTAGE OF NEW TECHNOLOGIES ALLOWING UNBIASED ANALYSIS OF BOTH HUMAN IMMUNE AND BACTERIAL FACTORS. THESE HIGH-THROUGHPUT TESTS WILL BE SUPPLEMENTED WITH FOCUSED TESTING OF HYPOTHESES THAT HAVE ARISEN THROUGH PRIOR RESEARCH, BY OUR GROUP AS WELL AS OTHERS. THOUGH THESE STUDIES WE WILL UNDERSTAND THE DIFFERENCES IN CO-INFECTIONS WITH OTHER TICK-BORNE DISEASES, SPECIFIC INFLAMMATORY PATTERNS, DISTRIBUTION OF CELL TYPES AND THEIR REACTIONS, AUTOANTIBODY FORMATION, AUTO-REACTING T CELLS, ANTIBIOTIC RESISTANCE AND PERSISTENCE OF B. BURGDORFERI, BINDING AND DISSEMINATION OF B. BURGDORFERI STRAINS AND SHEDDING OF PEPTIDOGLYCAN BETWEEN PATIENTS WITH PTLDS AND RLD. IN ADDITION, AS PART OF THIS PROCESS, WE WILL ALSO BE DEVELOPING ONE OF THE LARGEST, WELL CHARACTERIZED SPECIMEN BANKS THAT WILL BE SHARED WITH THE RESEARCH COMMUNITY FOR ADDITIONAL TESTING IN A WAY THAT RESULTS CAN BE AGGREGATED TO CONTINUALLY BROADEN OUR UNDERSTANDING OF PTLDS. OUR HIGHLY EXPERIENCED GROUP IS OPERATING UNDER NO ILLUSIONS ABOUT HOW DIFFICULT AND COMPLEX THIS STUDY WILL BE TO COMPLETE. HOWEVER, WE BELIEVE THAT THIS TYPE OF EFFORT IS NEEDED TO MOVE THE FIELD-- WHICH IS ESSENTIALLY NO CLOSER TO A CONSENSUS UNDERSTANDING OF PTLDS TODAY THAT IT WAS 30 YEARS AGO-- AND TO MAKE PROGRESS FOR THE HEALTH OF THE AFFLICTED PATIENTS.

TRAINING IN EDUCATION AND CRITICAL RESEARCH SKILLS

COMPARATIVE-EFFECTIVENESS OF POPULATION STRATEGIES TO IMPROVE DIET AND REDUCE CVD

MASTER SPECIFIC COOPERATIVE AGREEMENT BETWEEN TUFTS AND ARS - NUTRITION RESEARCH FOR HEALTHY AGING AND PREVENTION OF CHRONIC DISEASE

NUTRITION COLLABORATIVE RESEARCH SUPPORT PROGRAM-FOCUS ON ASIA

FACILITY UPGRADE FOR THE NEW ENGLAND REGIONAL BIOSAFETY LABORATORY - PROJECT SUMMARY THE NEW ENGLAND REGIONAL BIOSAFETY LABORATORY (NERBL) WAS ESTABLISHED IN 2007 ON THE TUFTS UNIVERSITY CUMMINGS SCHOOL OF VETERINARY MEDICINE (TU CSVM) NORTH GRAFTON MA CAMPUS. THIS FACILITY WAS ORIGINALLY DESIGNED FOR RESEARCH ON EMERGING INFECTIOUS DISEASES UNDER BSL2 AND BSL3 CONDITIONS; TO SUPPORT ANIMAL MODEL ABSL3 STUDIES; AND TO ALLOW LOCAL AND REGIONAL INVESTIGATORS ACCESS TO BIOCONTAINMENT FACILITIES THAT WERE NOT AVAILABLE WITHIN THEIR HOME INSTITUTIONS. OVER THE PAST 13+ YEARS, THE NERBL HAS EFFECTIVELY SERVED AS AN IMPORTANT RESOURCE FOR RESEARCHERS ACROSS TU AS WELL AS A VARIETY OF EXTERNAL STAKEHOLDERS, INCLUDING INDUSTRY SPONSORS. HOWEVER, SEVERAL CONSTRAINTS HAVE BEGUN TO HAMPER GROWTH AND SUSTAINABILITY OF ITS MISSION. THESE INCLUDE OUTDATED AND/OR NON-FUNCTIONAL LABORATORY EQUIPMENT, POOR EFFICIENCIES AND WORKFLOW IN THE VIVARIUM SPACES, AND AGING BUILDING SYSTEMS THAT REPRESENT SAFETY AND OPERATIONAL CONCERNS. AS SUCH, THE CENTRAL PURPOSE OF THIS APPLICATION IS TO UPGRADE OUR EXISTING FACILITY, PARTICULARLY ITS FOUNDATIONAL OPERATING SYSTEMS, AND TO MODERNIZE THE VIVARIUM AND LABORATORY SPACES WITH STATE-OF-THE-ART TECHNOLOGIES. TO ACCOMPLISH THIS, WE WILL: 1) UPGRADE THE BUILDING AUTOMATION SYSTEM, HVAC ACTUATORS/FILTERS/VALVES, FACILITY LIGHTING AND ELECTRICAL SYSTEMS, AND COMMUNICATION PLATFORMS; 2) MODERNIZE AND EXPAND THE VIVARIUM WITH NEW VENTILATED RACK SYSTEMS THAT ACCOMMODATE DISPOSABLE CAGING FOR SMALL ANIMALS TO REDUCE COSTS AND IMPROVE EFFICIENCIES, PURCHASE A BIOBUBBLE CONTAINMENT SYSTEM TO FACILITATE STUDIES USING LARGER ANIMALS, AND IMPLEMENT TELEMETRY FOR REMOTE MONITORING OF ANIMALS; 3) REPLACE OBSOLETE LABORATORY EQUIPMENT WITH MODERN COUNTERPARTS FOR HIGH THROUGHPUT IN CONTAINMENT, PERMITTING EACH BSL3 LABORATORY TO BE FULLY EQUIPPED AND FUNCTIONALLY INDEPENDENT, THEREBY MAXIMIZING RESEARCH OUTPUT, WORKFLOW, AND USER SAFETY; AND 4) IMPROVE CRITICAL LABORATORY SAFETY SYSTEMS WITH TECHNOLOGY UPGRADES THAT PROVIDE REDUNDANCY FOR DECONTAMINATION AND WASTE INACTIVATION. COMPLETION OF THESE SPECIFIC AIMS WILL ENSURE THAT THE NERBL CONTINUES TO ADVANCE EMERGING INFECTIOUS DISEASE RESEARCH FOR THE NEXT DECADE. WE WILL EXPAND ACCESS FOR INVESTIGATORS PERFORMING CUTTING-EDGE STUDIES BY LEVERAGING ADVANCED LABORATORY METHODS AND ANIMAL MODELS IN A SAFE, SECURE, AND TECHNOLOGICALLY SOUND ENVIRONMENT.

MASTER SPECIFIC COOPERATIVE AGREEMENT BETWEEN TUFTS AND ARS - NUTRITION RESEARCH FOR HEALTHY AGING AND PREVENTION OF CHRONIC DISEASE

ADMINISTRATIVE SUPPLEMENT TO ENHANCE IRACDA PROGRAM EVALUATION CAPACITY

GENETIC DISSECTION OF LIPOPOLYSACCHARIDE RESPONSE

HIGH ENERGY PHYSICS RESEARCH

ACT-NOW: AUTONOMOUS COGNITIVE TECHNOLOGIES FOR NOVELTY IN OPEN WORLDS

TUSM/T-NEMC CENTER FOR NEUROSCIENCE RESEARCH

DEVELOPMENT OF TECHNOLOGIES FOR EARLY DETECTION AND STATIFICATION OF BREAST CANCER

THE MULTIPLE ANTIBIOTIC RESISTANCE (MAR) REGULON

RETROVIRUS EVOLUTION AND CANCER

LEGACY EFFECTS OF CALERIE, A 2-YEAR CALORIE RESTRICTION INTERVENTION, ON HALLMARKS OF HEALTHSPAN AND AGING - PROJECT SUMMARY CALORIE RESTRICTION (CR) IS A PROMISING NUTRITIONAL STRATEGY WITH THE POTENTIAL TO SLOW THE AGING PROCESS. THE COMPREHENSIVE ASSESSMENT OF LONG-TERM EFFECTS OF REDUCING INTAKE OF ENERGY (CALERIE) TRIAL, FUNDED BY THE NATIONAL INSTITUTE ON AGING, WAS THE FIRST CLINICAL TRIAL TO DEMONSTRATE THE FEASIBILITY OF ACHIEVING SUSTAINED, MODERATE CR IN HEALTHY, YOUNG AND MIDDLE-AGED ADULTS WITHOUT OBESITY. DURING THE 2-YEAR CR INTERVENTION, PARTICIPANTS ACHIEVED 12% CR ON AVERAGE AND, COMPARED TO AN AD LIBITUM INTAKE CONTROL GROUP, EXPERIENCED REMARKABLE IMPROVEMENTS IN MARKERS OF HEALTHSPAN AND A SLOWER RATE OF BIOLOGICAL AGING. THE OVERARCHING GOAL OF THIS PROPOSED STUDY IS TO EXAMINE WHETHER 2 YEARS OF CR RESULTS IN LONG-TERM IMPROVEMENTS IN THE BIOLOGICAL, PHENOTYPIC, AND FUNCTIONAL HALLMARKS OF HUMAN AGING. WE HYPOTHESIZE THAT EXPOSURE TO A 2-YEAR CR INTERVENTION IN EARLY TO MID-ADULTHOOD RESULTS IN SUSTAINED LOWER RATES OF BIOLOGICAL AGING, DELAYED MANIFESTATIONS OF PHENOTYPIC AGING, SUPERIOR INDICES OF FUNCTIONAL AGING, AND GREATER QUALITY OF LIFE COMPARED TO AD LIBITUM INTAKE. TO TEST THIS HYPOTHESIS, WE WILL CONDUCT AN OBSERVATIONAL FOLLOW-UP STUDY OF CALERIE PARTICIPANTS 10 TO 15 YEARS AFTER THE END OF THEIR TRIAL PARTICIPATION. PARTICIPANTS FROM THE CALERIE CR GROUP WILL BE COMPARED WITH AN AD LIBITUM INTAKE COMPARISON GROUP COMPOSED OF THE CALERIE AD LIBITUM CONTROL GROUP AND A MATCHED COMMUNITY-DWELLING COHORT FROM THE BALTIMORE LONGITUDINAL STUDY OF AGING (BLSA). THE WELL- CHARACTERIZED BLSA COHORT IS INCLUDED AS A COMPARISON SAMPLE TO ADDRESS THE CONCERN THAT THE HIGHLY SCREENED CALERIE CONTROLS MAY HAVE BEEN HEALTHIER THAN THE GENERAL POPULATION AND HIGHLY MOTIVATED FOR BEHAVIOR CHANGE. THE BLSA ALSO HAS THE RIGOR, QUALITY CONTROL, AND SEVERAL OF THE SAME OUTCOME MEASUREMENTS AS THE CALERIE TRIAL TO FACILITATE COMPARISONS. THE PROPOSED CALERIE FOLLOW-UP STUDY WILL INCLUDE A COMPREHENSIVE SET OF PHYSICAL AND FUNCTIONAL ASSESSMENTS, INCLUDING RESTING METABOLIC RATE, BODY COMPOSITION, CARDIORESPIRATORY FITNESS, GRIP STRENGTH, AND COGNITIVE FUNCTION, IN ADDITION TO PSYCHOLOGICAL AND QUALITY-OF-LIFE MEASURES. BLOOD AND URINE ALSO WILL BE COLLECTED AND ANALYZED FOR MARKERS OF BIOLOGICAL AGING AND CARDIOMETABOLIC DISEASE RISK. COMPARISONS WILL BE MADE BETWEEN CALERIE CR PARTICIPANTS AND THE COMBINED AD LIBITUM INTAKE COMPARISON GROUP (THE CALERIE AD LIBITUM CONTROL GROUP AND THE BLSA COHORT). EVALUATING LEGACY EFFECTS OF THE CALERIE TRIAL WILL DETERMINE THE EFFECTIVENESS OF A CR INTERVENTION IN EARLY TO MID- ADULTHOOD FOR PREVENTING THE DEVELOPMENT OR DELAYING THE PROGRESSION OF AGE-RELATED CHRONIC DISEASE. THE PROPOSED TRIAL WILL AUGMENT THE CALERIE DATA AND BIOSPECIMEN REPOSITORY FOR FUTURE RESEARCH TO ADVANCE OUR UNDERSTANDING OF HUMAN AGING.

HIGH ENERGY PHYSICS AT TUFTS UNIVERSITY

BIODEGRADABLE COMMUNICATIONS SYSTEM

EXCLUSIVE BREASTFEEDING IS RANKED AS THE NUMBER ONE PREVENTATIVE CHILD SURVIVAL INTERVENTION WHILE APPROPRIATE AND TIMELY COMPLEMENTARY FEEDING IS RANKED AS NUMBER THREE. GLOBALLY, THE IMPLEMENTATION OF OPTIMAL INFANT AND YOUNG CHILD FEEDING (IYCF) CAN PREVENT UP TO 1.4 MILLION DEATHS ANNUALLY. MATERNAL BREASTFEEDING AND APPROPRIATE COMPLEMENTARY FEEDING PROVIDE OPTIMAL NUTRITION IN EARLY YEARS OF LIFE AND BENEFIT BOTH THE MOTHER AND THE INFANT LATER IN LIFE. TO ADDRESS JORDAN¿S NUTRITION CHALLENGES, USAID/JORDAN ANTICIPATES AWARDING TWO COMPANION ACTIVITIES. THE FIRST, COMMUNITY HEALTH AND NUTRITION, IS A FIVE-YEAR COOPERATIVE AGREEMENT TO WORK WITH COMMUNITIES AND HEALTH CARE PROVIDERS TO IMPROVE THE NUTRITIONAL STATUS OF CHILDREN UNDER FIVE AND PREGNANT AND LACTATING WOMEN BY IMPROVING BREASTFEEDING PRACTICES, INTRODUCING APPROPRIATE COMPLEMENTARY FOODS AT THE RIGHT TIME, AND ENSURING APPROPRIATE CHILD SPACING THROUGH POSTPARTUM FAMILY PLANNING (FP) AND CONTINUATION OF MODERN FORMS OF CONTRACEPTION.THE SECOND, DESCRIBED HERE, IS USAID¿S NUTRITION INNOVATION LAB WHICH WILL BE A COMPANION AWARD TO THE COMMUNITY HEALTH AND NUTRITION ACTIVITY, TO LINK PROGRAM LEARNING WITH PROGRAM IMPLEMENTATION, AND TO IMPROVE THE LEVEL OF PUBLIC HEALTH NUTRITION ACADEMIC KNOWLEDGE IN JORDAN

MEDICAL SCIENTIST TRAINING PROGRAM AT TUFTS UNIVERSITY

BEHAVIORAL NEUROBIOLOGY OF AGGRESSION: ALCOHOL, GABA, AND 5-HT

GENE SILENCING IN SCHISTOSOMES USING RNAI

A MULTILEVEL COMMUNITY ENGAGED INTERVENTION TO BUILD A SUSTAINABLE AND EQUITABLE FOOD ECONOMY WITH FOOD IS MEDICINE OFFERINGS IN THE MISSISSIPPI DELTA TO IMPROVE MINORITY HEALTH AND REDUCE DISPARITIES - PROJECT SUMMARY/ABSTRACT THE GOAL OF THIS PROJECT IS TO TEST WHETHER A MULTI-LEVEL, COMMUNITY-ENGAGED INTERVENTION TO BUILD A SUSTAINABLE FOOD ECONOMY WITH FOOD-IS-MEDICINE PROGRAMS IN THE MISSISSIPPI DELTA CAN IMPROVE MINORITY HEALTH AND REDUCE HEALTH DISPARITIES. OUR CENTRAL HYPOTHESIS IS THAT AN INTERVENTION DEVELOPED WITH ACTIVE COMMUNITY ENGAGEMENT TO INCREASE LOCAL PRODUCTION AND DISTRIBUTION OF FRUITS AND VEGETABLES (FV), WILL INCREASE FV CONSUMPTION AND DECREASE BODY MASS INDEX (BMI), HEMOGLOBIN A1C (HBA1C) AND HEALTH DISPARITIES AMONG PARTICIPATING ADULTS COMPARED TO CONTROL PARTICIPANTS OVER A 12-MONTH STUDY PERIOD. AIM 1: TO DESIGN A NOVEL INTERVENTION THAT BOLSTERS THE LOCAL FOOD ECONOMY AND DELIVERS FOOD-IS-MEDICINE PROGRAMMING TO A MINORITY POPULATION WITHIN COMMUNITIES WITH PERSISTENT DISADVANTAGE. USING THE PRINCIPLES AND PROCESSES OF COMMUNITY-ENGAGED RESEARCH, WE WILL UNITE COMMUNITY PARTNERS AND MEMBERS OF BOLIVAR, WASHINGTON, AND SUNFLOWER COUNTIES IN A LOCAL MULTI-SECTOR DELTA FOOD POLICY COUNCIL (FPC). THE FPC WILL DESIGN AND IMPLEMENT A MULTI-LEVEL INTERVENTION TO PROVIDE APPROPRIATE NUTRITION, FOCUSING ON LOCALLY GROWN FV, TO BUILD A SUSTAINABLE FOOD ECONOMY AND IMPROVE HEALTH OUTCOMES. AIM 2: TO TEST WHETHER THE NOVEL INTERVENTION REDUCES HEALTH DISPARITIES BY IMPROVING OUTCOMES RELATED TO OBESITY AND DIABETES AMONG A RURAL MINORITY POPULATION. WE WILL WORK COLLABORATIVELY WITH THE FPC TO IMPLEMENT AND EVALUATE A MULTI-LEVEL, COMMUNITY-ENGAGED, RANDOMIZED CONTROLLED INTERVENTION TARGETING 300 ADULTS (>25 Y) WITH FOOD INSECURITY, BMI >25, AND HBA1C)>5.7-8.5%. OUTCOME MEASURES ARE (*PRIMARY): INDIVIDUAL-LEVEL: INCREASE F+V CONSUMPTION*; DECREASE OBESITY (BMI)*, DIABETES RISK (HBA1C)*, AND SYSTOLIC BLOOD PRESSURE COMMUNITY-LEVEL: INCREASE PRODUCTION AND DISTRIBUTION OF FV; INSTITUTE ACCESS TO PRODUCE AND DECREASE FOOD INSECURITY; AND DECREASE HEALTH CARE UTILIZATION AIM 3: GENERATE A REPLICABLE AND SCALABLE FOOD ECONOMY MODEL TO REDUCE OBESITY AND IMPROVE DIABETES. THE MODEL WILL FOCUS ON ADULTS LIVING IN AREAS WITH DISADVANTAGE AND MAKE SUSTAINABLE FOOD-IS-MEDICINE POLICY RECOMMENDATIONS RELATED TO SNAP, MEDICARE/MEDICAID AND THE FARM BILL TO STATE AND FEDERAL LEGISLATURES. EXPECTED IMPACT: COMMUNITY-CENTERED EFFORTS THAT BUILD VITAL LOCAL FOOD ECONOMIES TO SUPPORT FOOD-IS-MEDICINE PROGRAMMING REPRESENT A MAJOR INNOVATION THAT INTEGRATES NUTRITION INTO THE HEALTHCARE SYSTEM AND SOCIAL SAFETY NET TO AMELIORATE DISEASE, MITIGATE DISPARITIES, AND SAVE BILLIONS OF DOLLARS IN HEALTH CARE EXPENDITURES ANNUALLY.

TUFTS CLINICAL AND TRANSLATION SCIENCE INSTITUTE (UL1)

SIGNALING PATHWAYS IN STAGES OF TUMORIGENESIS

IMMUNOREGULATION OF SCHISTOSOMIASIS

RETROVIRUS EVOLUTION

MODELS TO PREDICT PROTEIN BIOMATERIAL PERFORMANCE

ENABLING TRUSTED HUMAN-LIKE ARTIFICIAL TEAMMATES ** FAADC MIGRATION NOTE - ACTION TYPE:"1" TO "A", RECORD TYPE:"2", BUSINESS FUNDS INDICATOR:"NON", INDIVIDUAL RECIPIENT INDICATOR:"NO", RESEARCH AND DEVELOPMENT FUNDS INDICATOR:"YES", COMPETED OPPORTUNITY:"1" TO "C", NUMBER OF PROPOSALS OR APPLICATIONS:"1", AWARDING SUB-TIER AGENCY CODE "5700" DERIVED FROM AWARDING OFFICE CODE "FA9550", FUNDING SUB-TIER AGENCY CODE "5700" DERIVED FROM FUNDING OFFICE CODE "F4FGA0", PPOP COUNTRY CODE:"USA", SMALL BUSINESS INDICATOR:"O", SAM EXCEPTION:"X" **

NUTRITION RESEARCH FOR HEALTHY AGING AND PREVENTION OF CHRONIC DISEASE

CENTER FOR METABOLIC RESEARCH ON HIV AND DRUG USE

WIC GRANTS TO STATES (WGS)

STUDY OF CELL-TYPE SPECIFIC ALZHEIMER'S DISEASE GENETIC VARIANTS USING A NOVEL BIOENGINEERED MODEL OF IPSC-DERIVED NEURAL TISSUE

SPORE ASSEMBLY IN CLOSTRIDIUM DIFFICILE

CTSA INSTITUTIONAL MENTORED CAREER DEVELOPMENT PROGRAM (KL2)

MICROSENSOR ARRAYS FOR SALIVA DIAGNOSTICS

MECHANISMS OF GENOME INSTABILITY MEDIATED BY SIMPLE DNA REPEATS

MECHANISM OF DEVELOPMENTAL TOXICITY OF BISPHENOL-A

CTSA K12 PROGRAM AT TUFTS UNIVERSITY - PROJECT SUMMARY THE FUTURE BIOMEDICAL WORKFORCE REQUIRES INVESTIGATORS WHO CAN CONDUCT AND DRIVE INNOVATION IN FUTURE CLINICAL TRANSLATIONAL RESEARCH (CTR) AND SCIENCE (CTS), ARE SKILLED IN DISCUSSING RESEARCH WITH THOSE OUTSIDE THEIR OWN FIELD, AND THUS HAVE THE ABILITY TO CRITICALLY EXAMINE RESEARCH IN BOTH RELATED AND UNRELATED FIELDS. OUR ESTABLISHED TUFTS K12 PROGRAM HAS DEMONSTRATED SUCCESS IN TRAINING EARLY CAREER FACULTY WHO, AFTER TRAINING, REMAIN ENGAGED IN TRANSLATIONAL RESEARCH AND SCIENCE AIMED AT IMPROVING HEALTH. WE WILL BUILD UPON OUR TRAINING SUCCESSES THROUGH THE FOLLOWING SPECIFIC GOALS: 1. TRAIN INVESTIGATORS WHO CAN SERVE AS DOMAIN EXPERTS AND RIGOROUS RESEARCHERS, THEREBY ADVANCING THE UNDERSTANDING AND RIGOROUS IMPLEMENTATION OF TRANSLATIONAL SCIENCE AND RESEARCH METHODS, SPANNING THE SECTORS OF TRANSLATIONAL SCIENCE ACROSS ALL TUFTS CTSI PARTNERS 2. TRAIN K12 SCHOLARS IN TRANSLATIONAL SCIENCE TO PREPARE THEM TO SERVE AS SYSTEM THINKERS, BOUNDARY- CROSSERS, AND TEAM PLAYERS 3. PROVIDE K12 SCHOLARS WITH LEADERSHIP AND MANAGEMENT SKILLS NEEDED FOR SUSTAINED TRANSLATIONAL SCIENCE CAREERS, AND TO SERVE AS PROCESS INNOVATORS, AND SKILLED COMMUNICATORS 4. MENTOR NEWLY INDEPENDENT FACULTY TO DEVELOP THE NEXT GENERATION OF MENTORS TO FUTURE TRANSLATIONAL SCIENTISTS 5. BUILD A DIVERSE TRANSLATIONAL SCIENCE WORKFORCE WE WILL ACHIEVE THESE GOALS BY A FOCUSED, INTEGRATED AND COLLABORATIVE PROGRAM CAREER DEVELOPMENT PLAN THAT SUPPORTS SKILL DEVELOPMENT IN TRANSLATIONAL SCIENCE TO ENSURE THAT SCHOLARS GAIN PROFICIENCY IN DISCOURSE AND DISCOVERY ACROSS DISCIPLINES WHILE THEY ALSO DEVELOP DEEP EXPERTISE WITHIN THEIR OWN DOMAIN. THE CAREER DEVELOPMENT PLAN INCLUDES A COMBINATION OF INDEPENDENT RESEARCH PROJECT, DIDACTIC SEMINARS AND COURSES, AND MENTORING. THE CORE OF THE PLAN IS A MENTORING TEAM THAT INCORPORATES TEAM SCIENCE AND INCLUSIVE EXCELLENCE TO SUPPORT SELF-DIRECTED LEARNING UNDER THE SUPPORT OF A TEAM OF INDIVIDUALS WITH COMPLEMENTARY SKILLS IN TRANSLATIONAL SCIENCE, LEADERSHIP AND MANAGEMENT, AND STAKEHOLDER ENGAGEMENT AND COMMUNICATION. WE AIM TO APPOINT EIGHT SCHOLARS. ALL CANDIDATES WILL HAVE A FULL-TIME APPOINTMENT AT ONE OF OUR PARTNERING INSTITUTIONS. INITIAL APPOINTMENTS FOR ALL CANDIDATES WILL BE FOR TWO YEARS, WITH OPPORTUNITY FOR AN ADDITIONAL THIRD YEAR. THE OUTCOME OF OUR TRAINING WILL BE A DIVERSE GROUP OF INDEPENDENTLY FUNDED TRANSLATIONAL INVESTIGATORS ACROSS MULTIPLE DISCIPLINES WITHIN TUFTS CTSI AND WHO ARE HIGHLY SKILLED IN MULTI-DISCIPLINARY TEAM APPROACHES. THESE INVESTIGATORS WILL HAVE THE SKILLS REQUIRED TO ADVANCE INTERDISCIPLINARY TRANSLATIONAL SCIENCE THAT WILL ADDRESS THE COMPLEX CHALLENGES TO IMPROVING HEALTH.

NANOLIPIDOIDS-CONJUGATED MICRORNA ENHANCE ORAL AND CRANIAL BONE REGENERATION

BIOLOGICAL ACTIVITY OF HPV E7 IN HUMAN EPITHELIAL CELLS

SIGNALING MECHANISMS IN VIBRIO CHOLERAE PARALLEL QUORUM SENSING PATHWAYS

CNS EXOSOMES-MEDIATED ADAPTIVE IMMUNITY IN ALZHEIMER'S DISEASE (AD) - ABSTRACT ALZHEIMER’S DISEASE (AD) REMAINS ONE OF THE MOST UNMET MEDICAL CHALLENGES IN OUR SOCIETY. IN THE AD, NEUROINFLAMMATION HAS BEEN INCREASINGLY RECOGNIZED TO PLAY A CENTRAL ROLE IN THE PATHOGENESIS OF AD, IN ADDITION TO EXTRACELLULAR AMYLOID PLAQUES AND HYPERPHOSPHORYLATED TAU BASED NEUROFIBRILLARY TANGLES. ALTHOUGH THE ROLE OF INNATE IMMUNITY ESPECIALLY REPRESENTED BY MICROGLIA IS WELL-ESTABLISHED IN AD, IT IS FAR LESS UNDERSTOOD AND ESTABLISHED ABOUT WHETHER AND HOW THE T OR B CELL-MEDIATED ADAPTIVE IMMUNITY IS INVOLVED IN AD PATHOGENESIS. IN PARTICULAR, WHETHER THERE ARE BRAIN- AND AD-SPECIFIC ANTIGENS TO ACTIVATE ADAPTIVE IMMUNITY AND HOW THESE ANTIGENS TRAVEL TO PERIPHERAL REMAIN TO BE INVESTIGATED. EXOSOMES (SIZE 40-100 NM), A MAJOR TYPE OF SECRETED EXTRACELLULAR VESICLES (EVS), ARE DERIVED FROM INTRALUMINAL VESICLES (ILV) THAT ARE BUDDED INWARDLY FROM THE EARLY ENDOSOMAL COMPARTMENT AND ARE RELEASED FROM MULTIPLE VESICULAR BODIES (MVB) DURING THE MATURATION OF ENDOSOMES. EVS AND EXOSOMES SECRETED FROM VARIOUS CNS CELL TYPES HAVE EMERGED AS A NOVEL AND IMPORTANT INTERCELLULAR PATHWAY IN THE. EXOSOME-MEDIATED SECRETION HAS ALSO BEEN IMPLICATED IN INITIATION AND PROPAGATION IN AD. ALTHOUGH EXOSOMES SECRETED FROM VARIOUS PERIPHERAL CELL TYPES ESPECIALLY IMMUNE AND TUMOR CELLS TRIGGER IMMUNE RESPONSES, WHETHER AND HOW CNS-DERIVED EXOSOMES ARE IMMUNOGENIC REMAINS UNEXPLORED. BY EMPLOYING CELL-TYPE SPECIFIC ILV/EXOSOME REPORTER (HCD63-GFPF/F) MICE WE RECENTLY GENERATED, WE SHOWED THAT ASTROGLIA-DERIVED EXOSOMES ARE ASSOCIATED WITH AQUAPORIN 4+ (AQP4+) PERIVASCULAR END FEET/BLOOD VESSEL IN THE BRAIN. HCD63-GFP+ ASTROGLIAL EXOSOMES CAN ALSO BE DETECTED IN BLOOD SERUM OF LPS-INJECTED (BUT NOT CONTROL) GLAST-CREER+CD63-GFPF/+ MICE. EXCITINGLY, EXOSOMES SECRETED FROM “REACTIVE” ASTROGLIA (RAES) STRONGLY ACTIVATE CD4+ AND CD8+ T CELLS IN VITRO AND IN VIVO. BASED ON PREVIOUS STUDIES AND OUR PRELIMINARY RESULTS, WE PROPOSE TO INVESTIGATE THE FOLLOWING AIMS: 1) DETERMINE PATHOLOGICAL EFFLUX OF CNS CELL-TYPE SPECIFIC EXOSOMES FROM BRAIN AND THEIR ENTRY INTO PERIPHERAL CIRCULATION IN AD MODELS; 2) DETERMINE ANTIGENICITY OF AD- RELEVANT ASTROGLIAL EXOSOMES IN ACTIVATING T CELLS IN VITRO AND IN VIVO. WE HAVE GENERATED A LARGE AMOUNT OF PRELIMINARY DATA TO SUPPORT OUR RATIONALES AND TO DEMONSTRATE FEASIBILITY FOR PROPOSED AIMS. WE WILL EMPLOY MOUSE GENETICS, VIRUS INJECTIONS, IMMUNOHISTOCHEMICAL (IHC) ANALYSIS AND IN VIVO TWO-PHOTON IMAGING, PRIMARY CULTURES, FACS, AND BIOCHEMICAL APPROACHES TO INVESTIGATE THESE TWO AIMS. RESULTS FROM THIS PROJECT WILL DETERMINE THE EFFLUX CHANGES OF NEURON OR ASTROGLIAL EXOSOMES FROM THE BRAIN AND THESE EXOSOMES’ ENTRY INTO PERIPHERAL CIRCULATION IN AD MODELS. IN ADDITION, OUR CURRENT STUDY WILL INVESTIGATE HOW T CELLS RESPOND TO “REACTIVE” ASTROGLIAL EXOSOMES. AS REACTIVE ASTROGLIA IS COMMONLY OBSERVED IN NEURODEGENERATIVE DISEASES INCLUDING AD, THIS WILL POTENTIALLY UNVEIL NEW MECHANISMS HOW T CELLS ARE INVOLVED IN AD PATHOGENESIS AND HELP DEFINE SPECIFIC BRAIN SIGNALS TO ACTIVATE T CELLS IN AD, WHICH SUBSEQUENTLY FACILITATE THE THERAPEUTIC DEVELOPMENT.

STUDY OF TRANSMISSIBLE FORMS OF VIBRIO CHOLERAE

TUFTS BIRCWH PROGRAM

IN VIVO PROTON MRS STUDIES:CEREBRAL INJURY IN HIV INFECTION

DENTAL STEM CELLS AND TOOTH TISSUE ENGINEERING

ACTIN PEDESTAL FORMATION BY EHEC O157:H7

NEW MURI GRANT

INVESTIGATING THE PATHOLOGICAL CONSEQUENCES OF SEIZURE-INDUCED ACTIVATION OF THE HPA AXIS

LESION-CENTRIC OPTIMIZATION OF MULTIDRUG THERAPIES FOR TUBERCULOSIS

MOLECULAR ANALYSIS OF MICROBIAL PATHOGENS

LABORATORY FOR COMBINATORIAL DRUG REGIMEN DESIGN FOR RESISTANT AND EMERGING PATHOGENS - (A) OVERVIEW THE PAST TWO YEARS HAVE SHOWN THAT INFECTIOUS DISEASES ARE GLOBAL THREATS, REVEALING AN URGENT NEED TO IMPROVE PREPAREDNESS TO COMBAT UNKNOWN PATHOGENS. FURTHERMORE, THE ALARMING INCREASE IN INFECTIONS CAUSED BY ANTIMICROBIAL RESISTANT (AMR; SEE GLOSSARY, BELOW) PATHOGENS IN RECENT YEARS, EXACERBATED BY THE COVID-19 PANDEMIC, ILLUSTRATES THAT WE ARE ALSO ON THE VERGE OF LOSING OUR ABILITY TO TREAT INFECTIONS CAUSED BY KNOWN PATHOGENS. COMBINATION DRUG TREATMENT IS THE THERAPEUTIC MAINSTAY IN THE TREATMENT OF INFECTIONS CAUSED BY SEVERAL MICROBIAL PATHOGENS, INCLUDING HIV AND THE TUBERCULOSIS BACTERIUM. STILL, SYSTEMATIC AND EFFICIENT DEVELOPMENT OF SUCH TREATMENTS FOR AMR OR EMERGING PATHOGENS IS LACKING. TUFTS UNIVERSITY (TU) IS PROPOSING TO CONSTRUCT A NEW BIOMEDICAL RESEARCH FACILITY, THE LABORATORY FOR COMBINATORIAL DRUG REGIMEN DESIGN FOR RESISTANT AND EMERGING PATHOGENS (LCDRD), TO DESIGN AND DEVELOP NEW COMBINATORIAL THERAPEUTIC APPROACHES FOR BACTERIAL, VIRAL, FUNGAL, AND PARASITIC INFECTIONS AND TO ACCELERATE RESEARCH ON AMR AND EMERGING PANDEMIC PATHOGENS. THE LCDRD IS DESIGNED TO FACILITATE THE DEVELOPMENT OF NOVEL TREATMENTS FOR DIFFICULT-TO-TREAT INFECTIONS DUE TO PATHOGENS FROM BOTH ANIMALS AND HUMANS. IN ADDITION TO GENERATING NEW THERAPIES FOR AMR OR EMERGING PATHOGENS, THIS FACILITY WILL PROVIDE DIVERSE, WELL-CHARACTERIZED HUMAN BACTERIAL PATHOGENS WITH LINKED CLINICAL DATA FROM ACROSS ‘TUFTS-MEDICINE’, A STATE-WIDE NETWORK OF HOSPITALS SERVING DIVERSE POPULATIONS, FOR STUDY BY ACADEMIA AND INDUSTRY. THE STUART B. LEVY TUFTS CENTER FOR INTEGRATIVE MANAGEMENT OF ANTIMICROBIAL RESISTANCE (CIMAR) UNITES FACULTY FROM TU AND TUFTS MEDICAL CENTER (TMC), AS WELL AS AFFILIATE MEMBERS FROM ACROSS THE REGION AND NATION, WITH EXPERTISE IN BIOMEDICAL RESEARCH, ENGINEERING, HUMAN AND VETERINARY MEDICINE, GLOBAL HEALTH, ENVIRONMENTAL SURVEILLANCE, POLICY, AND EDUCATION, TO CATALYZE THE DEVELOPMENT OF NEW COMBINATORIAL DRUG STRATEGIES TO TREAT A WIDE RANGE OF PATHOGENS. WORKING WITH CIMAR IN LCDRD WILL BE THE NASCENT CENTER FOR EMERGING INFECTIOUS DISEASES AND RESPONSE (CEIDAR), WHICH ADDRESSES EMERGING AND EXPANDING INFECTIOUS DISEASE THREATS SUCH AS INSECT-BORNE BACTERIAL AND VIRAL PATHOGENS. CEIDAR INCLUDES THE TUFTS LYME INITIATIVE AND UTILIZES THE BSL-3 LEVEL TUFTS NEW ENGLAND REGIONAL BIOSAFETY LABORATORY (NERBL) AT TUFTS CUMMINGS SCHOOL OF VETERINARY MEDICINE IN GRAFTON, AN IMPORTANT RESOURCE FOR EXPANDING WORK. INSTITUTIONS AFFILIATED WITH CIMAR/CEIDAR SPAN A SPECTRUM OF ACADEMIC AND PHARMACEUTICAL INTERESTS AND, ALTHOUGH LOCATED LOCALLY AT TU, WILL ENHANCE TRANSDISCIPLINARY INTERACTIONS AMONG REGIONAL AND NATIONAL INVESTIGATORS AND ENTITIES. PROJECT GOALS: THE LCDRD WILL ENABLE SPECIALIZED AND COLLABORATIVE WORK ON EMERGING AND RESISTANT MICROBIAL PATHOGENS THAT IS REQUIRED TO GENERATE NEW COMBINATORIAL TREATMENTS. THE FACILITY WILL: 1) ENHANCE INTERACTION BETWEEN CLINICIANS AND BIOMEDICAL RESEARCHERS TO GENERATE THERAPEUTIC ANTIMICROBIAL DRUG REGIMENS, PARTICULARLY COMBINATION THERAPIES, AGAINST CDCS URGENT AND EMERGING THREAT PATHOGENS; 2) DEVELOP GENETIC AND SYSTEMS APPROACHES TO FACILITATE ‘PERSONALIZED MEDICINE’ FOR PATIENTS WITH DIFFICULT-TO-TREAT INFECTION; 3) PROVIDE A SPACE WHERE VISITING SCIENTISTS CAN RECEIVE HANDS-ON TRAINING, ALLOWING KNOWLEDGE DISSEMINATION INTRA-INSTITUTIONALLY, REGIONALLY, NATIONALLY, AND GLOBALLY; AND 4) INCREASE THE NATIONAL CAPACITY TO RESPOND TO INFECTIOUS DISEASE EMERGENCIES BY PROVIDING ACADEMIC AND INDUSTRIAL ENTITIES ACCESS TO LIBRARIES OF WELL-CHARACTERIZED ISOLATES FOR EMERGING PANDEMIC AND AMR PATHOGENS. AFFECTED SPACE AND REQUESTED EQUIPMENT: THE LCDRD WILL PROVIDE A MODERN, CENTRALIZED LABORATORY AND COLLABORATION CAPACITY FOR A MULTI-INSTITUTIONAL EFFORT TO UTILIZE STATE-OF-THE-ART RESEARCH TECHNOLOGIES TO GENERATE AND CHARACTERIZE NOVEL DRUG THERAPIES FOR PATHOGENS RESI

FATTY ACIDS AND MAJOR CARDIOVASCULAR OUTCOMES

HOST IMMUNITY TO EBV INFECTION IN VITRO AND IN VIVO

TUFTS POST-BACCALAUREATE RESEARCH EDUCATION PROGRAM

ROLE OF BAND 3 IN MALARIA INVASION OF RED BLOOD CELLS

A PLATFORM FOR THERAPEUTIC AGENTS THAT PROMOTE RAPID RECOVERY FROM BOTULISM

TAS::89 0222::TAS; A SINGLE-MOLECULE APPROACH FOR UNDERSTANDING AND UTILIZING SURFACE AND SUBSURFACE ABSORPTION TO CONTROL CHEMICAL REACTIVITY AND S

SEARCHING FOR PERSISTENCE IN LYME DISEASE

NUTRITION RESEARCH FOR HEALTHY AGING AND PREVENTION OF CHRONIC DISEASE

CTSA GRADUATE PROGRAM

ASTROCYTE-NEURON SIGNALING

DEVELOPMENT AND FIELD TESTING OF A NOVEL RESERVOIR TARGETED ANTIBIOTIC AGAINST BORRELIA BURGDORFERI

TESTING A BRIEF SUBSTANCE MISUSE PREVENTIVE INTERVENTION FOR PARENTS OF YOUTH

THIS GRANT IS A CONTINUATION OF N00014X14X1X0144 MORAL COMPETENCE IN COMPUTATIONAL ARCHITECTURES FOR ROBOTS: FOUNDATIONS, IMPLEMENTATIONS, AND DEMONS

GABAERGIC REGULATION OF GLUTAMINE SYNTHETASE AND ITS ROLE IN PREVENTING EPILEPSY

NUTRITION RESEARCH FOR HEALTHY AGING AND PREVENTION OF CHRONIC DISEASE

VITAMIN B12 STATUS, COGNITIVE DECLINE AND INCIDENT DEMENTIA

VOLTAGE IMAGING OF ASTROCYTE-NEURON INTERACTIONS

POSTDOCTORAL TRAINING IN GENERAL PEDIATRIC AND PUBLIC HEALTH DENTISTRY AND DENTAL HYGIENE

VITAMINS D AND K AND NEUROPATHOLOGICALLY-DEFINED ALZHEIMER AND OTHER DEMENTIAS IN OLDER PERSONS

BIOENGINEERED COMPOSITE ALVEOLAR BONE-TOOTH CONSTRUCTS FOR TOOTH REGENERATION

THIS ACTIVITY WILL SUPPORT RESEARCH AND DEVELOPMENT INNOVATIONS TO PREVENT AND TREAT NUTRITION VULNERABILITIES IN COMPLEX ENVIRONMENTS IN EAST AFRICA, SPECIFICALLY IN UGANDA, WHERE CHRONIC AND ACUTE MALNUTRITION AND FOOD SECURITY REMAIN A SUBSTANTIAL CHALLENGE.

DISSECTING YERSINIA YOP TARGETS IN NEUTROPHILS - ABSTRACT NEUTROPHILS (PMNS, POLYMORPHONUCLEAR CELLS) ARE PIVOTAL INNATE IMMUNE CELLS THAT DIRECTLY MEDIATE PATHOGEN CLEARANCE THROUGH RELEASE OF REACTIVE OXYGEN SPECIES (ROS), DEGRANULATION, NEUTROPHILIC EXTRACELLULAR TRAPS (NETS) AND PHAGOCYTOSIS. THE BACTERIAL PATHOGEN, YERSINIA PSEUDOTUBERCULOSIS (YPTB) ANTAGONIZES THESE ANTIMICROBIAL ACTIONS BY INJECTING CRITICAL VIRULENCE PROTEINS, CALLED YOPS, INTO PMNS. WE SEEK TO UNDERSTAND MECHANISMS THAT MEDIATE CLEARANCE OF BACTERIAL PATHOGENS IN TISSUE INFECTION BY UNDERSTANDING THE PROCESSES THAT ARE DISRUPTED BY YOPH AND YOPO. WE HAVE SHOWN THAT SKAP2 IS ONE ESSENTIAL TARGET OF YOPH IN PMNS IN TISSUE INFECTION; HOWEVER, SKAP2 IS NOT THE ONLY ESSENTIAL TARGET OF YOPH IN TISSUE INFECTION. MISSENSE MUTATIONS IN SKAP2 ARE ASSOCIATED WITH THE DEVELOPMENT OF AUTOIMMUNE DISORDERS AND CANCERS. THIS SUGGESTS THAT PMN DYSFUNCTION DOWNSTREAM OF SKAP2 SIGNALING HAS WIDE RANGING IMPLICATIONS BEYOND INFECTION CONTROL. WE HAVE FURTHER SHOWN THAT SKAP2-DEPENDENT MECHANISMS IN NEUTROPHILS ARE CRITICAL FOR LIMITING GROWTH OF ANOTHER GRAM-NEGATIVE PATHOGEN, KLEBSIELLA PNEUMONIAE (KP), IN LUNGS. USING PMNS DERIVED FROM MYELOID PROGENITOR (MP) HEMATOPOIETIC STEM CELLS, WE FOUND THAT SKAP2 IS ESSENTIAL FOR EXTRACELLULAR (ROS) PRODUCTION BUT IS NOT REQUIRED FOR DEGRANULATION AFTER KP INFECTION. SURPRISINGLY, SKAP2 IS REQUIRED FOR SYK PHOSPHORYLATION AFTER INFECTION BY KP, BUT NOT FOR SYK PHOSPHORYLATION AFTER STIMULATION OF CLRS AND INTEGRIN RECEPTORS, INDICATING THAT NEUTROPHIL RECOGNITION OF KP IS VIA A DISTINCT RECEPTOR, POSSIBLY A G PROTEIN COUPLED RECEPTOR (GPCR). THE OBJECTIVE OF THIS APPLICATION IS TO USE OUR EXPERTISE IN MURINE INFECTION MODELS, MP-PMN GENETIC MANIPULATION, BACTERIAL GENETICS AND LIVE-CELL VISUALIZATION OF PROTEIN COMPLEXES, TO UNDERSTAND PATHWAYS IN PMNS THAT ARE TARGETED BY YOPH AND YOPO. WE WILL FURTHER INVESTIGATE WHETHER THESE TARGETS PLAY CRUCIAL ROLES IN THE CONTROL KP. TO THIS END, OUR SPECIFIC AIMS ARE TO (1) DISSECT THE MODULAR FUNCTIONS OF SKAP2 REQUIRED FOR GENERATING ANTI-MICROBIAL RESPONSES IN NEUTROPHILS AFTER INFECTION WITH KP. (2) UNDERSTAND THE EFFECTS OF YOPO ON GPCR SIGNALING IN PMNS DURING MURINE INFECTION. (3) IDENTIFY THE SKAP2-INDEPENDENT PATHWAYS THAT ARE TARGETED BY YOPH TO INACTIVATE NEUTROPHIL DEGRANULATION. AFTER COMPLETION OF THESE STUDIES, WE WILL UNDERSTAND HOW SKAP2 AND OTHER YOP-TARGETED PROTEINS WORK IN PMNS TO CONTROL INFECTION BY KP AND YPTB. A THOROUGH UNDERSTANDING OF MOLECULAR MECHANISMS THAT SIGNAL FOR THE RELEASE OF THE TISSUE DAMAGING BACTERICIDAL FACTORS, ROS AND GRANULES, BY PMNS DURING INFECTION SHOULD LEAD TO NOVEL AND TARGETED APPROACHES TO MANIPULATE THESE PATHWAYS TO ENHANCE THESE ACTIVITIES DURING INFECTION WITH MULTIDRUG RESISTANT BACTERIA AND TO STOP EXCESSIVE DAMAGE DUE TO UNCONTROLLED PMN RESPONSES IN A VARIETY OF AUTO-IMMUNE DISEASES.

REGULATION OF LPS-RESPONSES BY ZBP1 - PROJECT SUMMARY THE GOAL OF THIS PROPOSAL IS INVESTIGATION OF THE MECHANISM OF ZBP1-MEDIATED RESPONSE TO LPS AND PROTECTION FROM BACTERIAL INFECTION THAT IS PROVIDED BY ZBP1. OUR PUBLISHED AND PRELIMINARY DATA CHARACTERIZE A NOVEL NONCANONICAL ACTIVATION FO CASPASE 8 IN RESPONSE TO LPS, WHICH RESULTS IN THE PYROPTOTIC CELL DEATH IN MACROPHAGES. IN FURTHER INQUIRY, WE IDENTIFIED THAT CONTAINING CASP8 PRO-DEATH COMPLEX II THAT ASSEMBLES IN RESPONSE TO LPS, IS NOT DEPENDENT ON TNFR1 AS WAS WIDELY ACCEPTED SO FAR, BUT RATHER ON TRIF THUS MAKING TRIF A CENTRAL COMPONENT OF THEIS ACTIVATION PATHWAY. TO REFLECT THE REQUIREMENT FOR TRIF IN COMPLEX II FORMATION AND ACTIVATION OF CASP8, WE TERMED THIS NEW PYROPTOSIS-INDUCING COMPLEX THE “TRIFOSOME”. IN FURTHER MECHANISTIC INQUIRY, WE FOUND THAT THE NUCLEIC ACID SENSOR, ZBP1, WHICH THUS FAR HAS BEEN IMPLICATED ONLY IN VIRAL INFECTIONS, PLAYS A SIGNIFICANT ROLE IN THE FORMATION OF THE TRIFOSOME COMPLEX BY SHUTTLING RIPK1 TO TRIF. THE RELIANCE OF COMPLEX II FORMATION ON ZBP1 RAISED A QUESTION WHETHER ZBP1 MEDIATES INFLAMMATORY RESPONSES TO LPS AS WELL. IN SUPPORT OF THIS HYPOTHESIS, OUR PRELIMINARY DATA SHOW THAT ZBP1 MEDIATES LPS- INDUCED INFLAMMATORY RESPONSES, THUS PROVIDING RATIONALE FOR FURTHER IN VIVO INVESTIGATIONS OF THE ROLE THAT ZBP1 MIGHT PLAY IN RESPONSES TO LPS AND YERSINIA INFECTION. TO ADDRESS WHETHER ZBP1-MEDIATED RESPONSE TO LPS PROVIDES PROTECTION FROM THE BACTERIAL INFECTION, WE PROPOSE 2 AIMS. IN AIM 1, WE WILL INVESTIGATE ZBP1- MEDIATED IN VITRO RESPONSE TO LPS USING DOUBLE KNOCKOUT AND GENE-SILENCING APPROACH. WE WILL USE ZBP1- SPECIFIC IMMUNOPRECIPITATION IN ORDER TO DETERMINE THE COMPONENTS OF ZBP1-INTERACTOME. DETERMINE THE CONTRIBUTION OF ZBP1 TO LPS-INDUCED IMMUNE RESPONSE, WHICH WILL INCLUDE ELUCIDATION SPECIFIC ROLE OF ZBP1 IN MEDIATING TRIF-DEPENDENT AND TRIF-INDEPENDENT RESPONSES. IT WILL ALSO INCLUDE DELINEATION OF THE ROLE OF ZBP1 IN THE RIPK1-SPECIFIC RESPONSE TO LPS. INCLUDING UNDERSTANDING THE ROLES OF THE FUNCTIONAL DOMAINS OF ZBP1 IN THIS PATHWAY, ANALYSIS OF THE RECRUITMENT OF ZBP1 INTO THE ENDOSOMAL TRIFOSOME COMPLEX, AND CHARACTERIZATION OF THE ZBP1-DEPENDENT CHANGES IN HOST RESPONSE TO BACTERIAL INFECTION IN VIVO. IN THE SECOND AIM, WE WILL CAPITALIZE ON OUR PRELIMINARY FINDINGS AND WILL FURTHER INVESTIGATE HOW THE KINETICS OF RESPONSE TO LSP THAT IS CONFERRED BY ZBP1 CONFERS SENSITIVITY TO LPS-INDUCED TOSICITY I VIVO, AND WHETHER THIS SENSITIVITY PROVIDES PROTECTION FROM GRAM-NEGATIVE INFECTION IN VIVO. THESE STUDIES WILL HELP ESTABLISHING THE ROLE OF ZBP1 IN HOST RESPONSE TO BACTERIAL INFECTION AND WILL POSITION ZBP1 AT THE CROSSTALK OF DIFFERENT IMMUNE RESPONSE PATHWAYS.

THE IMPACT OF OMEGA THREE FATTY ACIDS ON VASCULAR FUNCTION AND CIMT IN HIV

FUTUREPROOFING HEALTH: DEVELOPING A CENTER FOR RESILIENT HEALTH IN DISASTERS - ABSTRACT: OVERALL THE GOAL OF THE CENTER FOR CLIMATE AND HEALTH GLOBAL RESEARCH ON DISASTERS (CORD) IS TO DEVELOP ACTION-ORIENTED STRATEGIES TO PROTECT HEALTH AND BUILD RESILIENCE IN CLIMATE-RELATED DISASTERS. CLIMATE CHANGE IS INCREASING THE FREQUENCY AND SEVERITY OF DISASTERS, AND UNDER-SERVED POPULATIONS OF THE GLOBAL SOUTH ARE MOST AT RISK FOR RESULTING HEALTH CALAMITIES. CORD WILL ADDRESS THE CRITICAL UNMET NEED FOR DATA THAT ACCURATELY REPORTS CURRENT CLIMATE-ASSOCIATED HEALTH OUTCOMES AND SUPPORTS THE DEVELOPMENT OF FEASIBLE, ACTIONABLE, CULTURALLY APPROPRIATE ANTICIPATORY ACTION PLANS TO PREVENT AND/OR AMELIORATE THESE HEALTH IMPACTS IN CLIMATE-RELATED DISASTERS. THE OBJECTIVE IS TO BUILD RESEARCH INFRASTRUCTURE TO ENABLE CUTTING-EDGE RESEARCH IN 6 CASE STUDIES CONDUCTED IN UNDER-SERVED AT RISK COMMUNITIES IN THE GLOBAL SOUTH. THE RATIONALE IS THAT THIS GLOBAL, TRANS-DISCIPLINARY, VIRTUAL CONSORTIUM OF 7 UNIVERSITIES FROM AROUND THE WORLD WILL PROVIDE A UNIQUE AND VALUABLE SOURCE OF DATA AND PERSPECTIVES THAT WILL INFORM POLICY, PRACTICE, AND SCIENCE RELEVANT TO UNDER-SERVED POPULATIONS. THE OVERALL AIMS ARE TO: 1) BUILD TRANSDISCIPLINARY, TRANSNATIONAL PARTNERSHIPS BETWEEN ACADEMIA, POLICY MAKERS, COMMUNITY MEMBERS, AND PRACTITIONERS; 2) BUILD DATA ANALYSIS TOOLS AND METHODOLOGIES FOR DATA COLLECTION, COMMUNITY-ENGAGED RESEARCH, COMPILATION, ANALYSIS, AND COMMUNICATION; AND 3) BUILD HUMAN CAPACITY TO EFFECTIVELY COLLABORATE ACROSS DISCIPLINES, CULTURES, AND GEOGRAPHIES. CORD WILL HAVE 4 OPERATING CORES. AN ADMINISTRATIVE CORE WILL PROVIDE STRATEGIES AND ORGANIZATIONAL STRUCTURES TO ESTABLISH, MANAGE AND SUPPORT CORD. A RESEARCH PROJECT WILL STUDY ANTICIPATORY ACTION SYSTEMS, DIFFERENTIATE HEALTH IMPACTS, DELINEATE COMMUNITY ACTIONS, AND DETERMINE THE ROLE OF HEALTH GOVERNANCE SYSTEMS IN THE TARGET COMMUNITIES. A COMMUNITY ENGAGEMENT CORE WILL ESTABLISH COLLABORATIONS WITH COMMUNITY LEADERS, HUMANITARIAN PRACTITIONERS, AND POLICYMAKERS IN ORDER TO EFFECT SOCIAL CHANGE. AN INNOVATED LEADERS NETWORK CORE WILL BUILD RESEARCH CAPACITY BY DEVELOPING AND SUPPORTING THE NEXT GENERATION OF RESEARCHERS, PRACTITIONERS AND POLICY MAKERS IN CLIMATE, HEALTH AND DISASTERS. THE PROPOSED WORK IS INNOVATIVE IN ITS MULTI-NATIONAL LEADERSHIP DESIGN, ITS STUDY OF NOVEL ANTICIPATORY ACTION SYSTEMS FOR DISASTERS, AND ITS COMMITMENT TO FUTURE LEADERS AND COMMUNITY ENGAGEMENT. THE PROPOSED WORK IS SIGNIFICANT BECAUSE IT WILL ESTABLISH NOVEL TRANS-DISCIPLINARY METHODOLOGIES TO WORK WITH COMMUNITIES TO DOCUMENT HEALTH IMPACTS ON DIFFERENT POPULATIONS AND THE CONTEXTUAL AND GOVERNANCE FOUNDATION THAT IS NECESSARY FOR SUCCESSFUL ADAPTATION TO CLIMATE CHANGE. THESE RESULTS WILL INFLUENCE THE DESIGN OF CLIMATE PROGRAMS BY THE COLLABORATING PARTNERS AND WILL SET THE STAGE FOR FUTURE RESEARCH ON THESE TOPICS IN THE CONTEXT OF OTHER ADAPTATION INTERVENTIONS. THE EXPECTED OUTCOME IS THAT THE ESTABLISHED PARTNERSHIPS WILL PREVENT NEGATIVE HEALTH OUTCOMES DURING DISASTERS AND PROMOTE HEALTH EQUITY IN UNDER-SERVED REGIONS AROUND THE WORLD.

NUTRITION-HORTICULTURE COLLABORATIVE RESEARCH PROGRAM

WIC GRANTS TO STATES (WGS)

A LONG NONCODING RNA AMERLIORATES PERIODONTITIS VIA DISTINCT EPIGENETIC PATHWAYS - NEARLY 50% OF AMERICAN ADULTS OVER AGE 30 HAVE PERIODONTAL DISEASE (PD). THE BASIC PATHOLOGY OF PD IS EXCESSIVE ALVEOLAR BONE RESORPTION LEADING TO TOOTH LOSS. FURTHERMORE, PD CAN TRIGGER GENERAL INFLAMMATION, ADVERSELY INFLUENCING CARDIOVASCULAR, CENTRAL NERVOUS, REPRODUCTIVE AND ENDOCRINE SYSTEMS. OUR LABORATORY HAS EXPLORED A VARIETY OF STRATEGIES FOR TREATING THIS DISEASE AND IS STILL ACTIVELY SEARCHING FOR A MORE EFFECTIVE AND PRACTICAL THERAPY WITH MINIMAL SIDE EFFECTS TO CURE THE DISEASE. LONG NONCODING RNAS (LNCRNAS) ARE A FAMILY OF NON-PROTEIN-CODING TRANSCRIPTS WITH THE LENGTH LONGER THAN 200 NUCLEOTIDES. LNCRNAS PARTICIPATE IN A WIDE REPERTOIRE OF BIOLOGICAL PROCESSES AND PLAY IMPORTANT ROLES IN GENE EXPRESSION AND POSTTRANSCRIPTIONAL PROCESSES AND ARE ALSO IMPLICATED IN THE PATHOGENESIS OF MANY DISEASES. HOWEVER, THE FUNCTIONS OF LNCRNAS IN DENTAL DISEASES ARE JUST BEGINNING TO BE UNCOVERED. LNCRNA ANRIL WAS THE FIRST SHARED GENETIC RISK FACTOR OF ATHEROSCLEROSIS, PD, DIABETES AND CANCERS, THEREBY COINED TO APCD. OUR LABORATORY HAS PERFORMED EXTENSIVE PRELIMINARY STUDIES INCLUDING STUDIES ON LNCRNA-APDC KNOCKOUT MICE. OUR HYPOTHESIS IS THAT LNCR-APDC INHIBITS INFLAMMATION, OSTEOCLASTIC BONE RESORPTION AND PROMOTES OSTEOGENESIS AND ALVEOLAR BONE REGENERATION THROUGH SPECIFIC EPIGENETIC PATHWAYS, BY WHICH EFFICIENTLY TARGETING THE PATHOPHYSIOLOGY OF PERIODONTITIS. AIM 1 WILL DETERMINE THE FUNCTIONS OF LNCR-APDC IN PERIODONTITIS VIA LOSS- AND GAIN-OF-FUNCTION APPROACHES. NEXT GENERATION RNA-SEQ WILL BE PERFORMED TO ELUCIDATE THE EXPRESSION PATTERNS OF THE PARTICIPATING GENES AND CELLULAR PATHWAYS ALTERED BY THE LNCRNA DYSREGULATION. AIM 2 WILL USE STATE-OF-THE-ART TECHNIQUES TO DETERMINE THE CELLULAR LOCALIZATION OF LNCR-APDC AND DECIPHER THE MECHANISMS BY CHARACTERIZING THE PROTEIN AND RNA BINDING PARTNERS AND CHROMOSOMAL REGIONS REGULATED BY THE LNCR-APDC. AIM 3 WILL TEST THE THERAPEUTIC EFFECTS OF LNCR- APDC IN PERIODONTITIS TO DETERMINE LNCR-APDC’S EFFECT ON INFLAMMATION, OSTEOCLASTIC BONE RESORPTION AND ALVEOLAR BONE REGENERATION. THE RESULTS WILL PROVIDE A PARADIGM SHIFT AND ADVANCE THE RESEARCH FIELD VERTICALLY IN THREE WAYS. FIRSTLY, WE HAVE INITIALLY FOUND THAT LNCR-APDC COULD PLAY A PIVOTAL ROLE IN CELL DIFFERENTIATION AND PROLIFERATION IN PD. HOWEVER, HOW THIS LNCRNA IS INVOLVED IN PD PROGRESSION IS VIRTUALLY UNKNOWN. THEREFORE, THE RESULTS WILL REVEAL A NOVEL PATHOLOGICAL MECHANISM OF PD DETERIORATION AND PROGRESSION. SECONDLY, WE WILL DECIPHER THE PATHWAYS OF LNCR-APDC MODULATING GENE CLUSTERS IN DIFFERENT CELLS PLAYING ACTIVE ROLES IN THE PERIODONTAL MICROENVIRONMENT AND THEIR ROLES IN THE PD PROGRESSION, WHICH WILL LEAD TO THE DISCOVERY OF NOVEL THERAPEUTIC TARGETS. FINALLY, WE WILL EXAMINE THE POTENTIAL UTILITY OF OUR NEWLY CONSTRUCTED ADENOVIRUS CONJUGATED LNCR-APDC, AS A SAFE AND EFFECTIVE THERAPEUTIC MEASURE FOR PD IN DENTAL CLINICS. AN INTERDISCIPLINARY TEAM OF INVESTIGATORS WITH COMPLEMENTARY AND SYNERGISTIC SKILLS WILL CONDUCT THE STUDIES (JAKE CHEN – EXPERIMENTAL ORAL PATHOLOGY AND BONE BIOLOGY; QISHENG TU – CELL AND MOLECULAR BIOLOGY; THOMAS VAN DYKE – PERIODONTOLOGY AND RNA-SEQUENCING; HANS JOHANSSON – RNA BIOLOGY AND LNCRNA FISH).

?REGULATION OF PROTEIN QUALITY CONTROL BY THE VCP AAA-ATPASE?

PREDICT TO PREVENT: DYNAMIC SPATIOTEMPORAL ANALYSES OF OPIOID OVERDOSE TO GUIDE PRE-EMPTIVE PUBLIC HEALTH RESPONSES - PREDICT TO PREVENT: DYNAMIC SPATIOTEMPORAL ANALYSES OF OPIOID OVERDOSE TO GUIDE PRE-EMPTIVE PUBLIC HEALTH RESPONSES PROJECT SUMMARY/ABSTRACT OPIOID OVERDOSE (OD) FATALITIES HAVE REACHED CRISIS LEVELS IN ALL SOCIOECONOMIC AND GEOGRAPHIC COMMUNITIES IN THE US. BY UTILIZING A FIRST-OF-ITS-KIND STATEWIDE PUBLIC HEALTH DATA WAREHOUSE (PHD) WITH MULTIPLE LINKED ADMINISTRATIVE DATASETS AND STATE-OF-THE-ART BAYESIAN SPATIOTEMPORAL MODELS, WE ARE IN A UNIQUE POSITION TO FILL IN THE FUNDAMENTAL GAPS IN THE FIELD’S ABILITY TO RAPIDLY IDENTIFY CURRENT OD PATTERNS, PREDICT FUTURE OD EPIDEMICS, AND EVALUATE THE EFFECTIVENESS OF PUBLIC HEALTH AND CLINICAL INTERVENTIONS. IN MASSACHUSETTS (MA), THE STATE LEGISLATURE ENACTED POLICY IN 2015 THAT PROVIDED AUTHORIZATION TO THE MA DEPARTMENT OF PUBLIC HEALTH (MDPH) TO DEVELOP A MASSIVELY LINKED ADMINISTRATIVE DATASET TO ALLOW PUBLIC HEALTH OFFICIALS AND POLICYMAKERS TO BETTER UNDERSTAND THE EXTENT OF AND CONTRIBUTORS TO THE OPIOID OD EPIDEMIC. THE PHD WAREHOUSE, REPRESENTING 98% OF THE MA POPULATION, CURRENTLY LINKS DATA FROM 25+ DISTINCT SOURCES (E.G., DEATH RECORDS, ALL-PAYER CLAIMS, POST-MORTEM TOXICOLOGY, HOSPITAL DISCHARGES, AND THE PRESCRIPTION MONITORING PROGRAM). SUPPORTED BY STRONG PRELIMINARY STUDIES DEMONSTRATING THE POWER OF THE PHD AND OUR STRONG PARTNERSHIP WITH MDPH, WE AIM TO DEVELOP A NEW POPULATION HEALTH ANALYTIC FRAMEWORK TO SUPPORT OPIOID OD CONTROL IN MA THAT CAN BE GENERALIZABLE TO OTHER PARTS OF THE COUNTRY. OUR SPECIFIC AIMS ARE TO: 1) DEVELOP A BAYESIAN MULTILEVEL SPATIOTEMPORAL MODEL TO IDENTIFY INDIVIDUAL, INTERPERSONAL, COMMUNITY, AND SOCIETAL FACTORS THAT CONTRIBUTE TO OPIOID OD; 2) DEVELOP AN EFFICIENT BAYESIAN SPATIOTEMPORAL MODEL TO IDENTIFY TIME- SPACE OD CLUSTERS, AND EXTEND THE MODEL TO CONSTRUCT A DYNAMIC PREDICTIVE MODEL; AND, 3) EVALUATE AND PREDICT POLICY AND INTERVENTION EFFECTS THROUGH MODEL-BASED SIMULATION STUDIES TO PROVIDE PRACTICAL GUIDANCE AND DECISION-MAKING SUPPORT TO PUBLIC HEALTH OFFICIALS. AIMS 1, 2 AND 3 CAN BE EASILY ADOPTED AND REPRODUCED BY USERS IN OTHER PUBLIC HEALTH JURISDICTIONS AND SECTORS TO FOSTER CROSS-SECTOR, CROSS-AGENCY OPIOID OD CONTROL. OUR APPROACH IS INNOVATIVE DUE TO THE USE OF PHD AND SOPHISTICATED BAYESIAN SPATIOTEMPORAL MODELING APPROACHES. THE PROPOSED STUDY IS HIGHLY SIGNIFICANT, BECAUSE IT IS CONCEPTUALIZED TO IMPROVE CURRENT AND FUTURE PUBLIC HEALTH PRACTICE, FACILITATING DATA-DRIVEN AND EVIDENCE-BASED IMPLEMENTATION SCIENCE INTERVENTIONS IN THE LOCATIONS AT GREATEST RISK AND AT THE TIME WHEN THEY ARE MOST NEEDED. OUR RESULTS CAN IMMEDIATELY AND SIGNIFICANTLY INFLUENCE OPIOID OD PREVENTION POLICIES AND PRACTICES, GUIDING PRE-EMPTIVE PUBLIC HEALTH AND CLINICAL RESPONSES. WE WILL DEVELOP OUR VISUALIZATION TOOLS, ANALYTICAL APPROACHES, AND RELATED CODE, IN COLLABORATION WITH MDPH AND OUR COMMUNITY ADVISORY BOARD (CAB), TO ENHANCE PHD CAPABILITIES AND IMPROVE DISSEMINATION OF FINDINGS. OUR TOOLS, APPROACHES, AND CODE WILL ALSO BE MADE AVAILABLE FOR NATIONAL DISSEMINATION, PROVIDING PARADIGM SHIFTING APPROACHES TO ADDRESS THE OPIOID CRISIS. OUR RESEARCH DIRECTLY ADDRESSES NIDA’S GOAL TO “DEVELOP NEW AND IMPROVED STRATEGIES TO PREVENT DRUG USE AND ITS CONSEQUENCES.”

THE MOLECULAR REGULATION OF HORIZONTAL BASAL CELL ACTIVATION IN THE OLFACTORY EPITHELIUM

MOLECULAR BASIS OF METAL ACQUISITION BY AN INTRAVACUOLAR PATHOGEN

NUTRITION RESEARCH FOR HEALTHY AGING AND PREVENTION OF CHRONIC DISEASE

NUTRITION RESEARCH FOR HEALTH AGING AND PREVENTION OF CHRONIC DISEASE

IMPACT OF BACTERIOPHAGES ON VIRULENCE AND TRANSMISSION OF VIBRIO CHOLERAE

STRUCTURE, ANTIGENICITY, AND FUNCTION OF HCMV FUSOGEN GB - PROJECT SUMMARY/ABSTRACT HUMAN CYTOMEGALOVIRUS (HCMV) IS A HIGHLY SUCCESSFUL HUMAN PATHOGENS THAT INFECTS MUCH OF THE WORLD’S POPULATION FOR LIFE. WHILE OFTEN ASYMPTOMATIC, HCMV INFECTIONS CAN CAUSE SEVERE DISSEMINATED DISEASE IN IMMUNOCOMPROMISED PATIENTS, E.G., TRANSPLANT RECIPIENTS, AND DEVELOPMENTAL ABNORMALITIES IN NEONATES. HENCE, THERE IS AN URGENT NEED FOR PROPHYLACTICS TO PREVENT VIRAL TRANSMISSION, ESPECIALLY FROM MOTHER TO FETUS. HCMV GLYCOPROTEIN B (GB) IS BOTH A KEY VIRAL PENETRATION PROTEIN AND A DOMINANT ANTIGEN FOR HOST DEFENSE. UNSURPRISINGLY, GB IS A COMPONENT OF ALL CURRENT HCMV VACCINE CANDIDATES. HOWEVER, VACCINE EFFORTS ARE STYMIED, AT LEAST IN PART, BY AN INCOMPLETE UNDERSTANDING OF GB-SPECIFIC IMMUNE RESPONSES. MOREOVER, THE MECHANISTIC CONTRIBUTIONS OF GB TO MEMBRANE FUSION REQUIRE FURTHER CLARIFICATION. THESE GAPS IN OUR KNOWLEDGE OF BOTH GB FUNCTION AND ANTIGENICITY LARGELY STEM FROM THE RELIANCE OF RESEARCH ON THE INACTIVE, POSTFUSION FORM OF GB THAT CANNOT ADEQUATELY RECAPITULATE THE ACTIVE, PREFUSION FORM. WE HAVE SUCCESSFULLY ENGINEERED SOLUBLE HCMV GB ECTODOMAIN IN A PREFUSION FORM. HERE, WE PROPOSE TO CHARACTERIZE ITS STRUCTURE, ANTIGENICITY, AND THE MECHANISMS THAT CONTROL ITS ACTIVITY. IN AIM 1, WE WILL DETERMINE THE HIGH-RESOLUTION STRUCTURES OF THE PREFUSION HCMV GB AND ITS COMPLEXES WITH KNOWN NEUTRALIZING ANTIBODIES. WE WILL ALSO STABILIZE PREFUSION GB FOR DOWNSTREAM APPLICATIONS (BIOCHEMICAL RESEARCH AND IMMUNOGEN DEVELOPMENT). IN AIM 2, WE WILL ISOLATE AND CHARACTERIZE PREFUSION-GB-SPECIFIC NEUTRALIZING ANTIBODIES FROM HCMV-SEROPOSITIVE DONORS. IN AIM 3, WE WILL INVESTIGATE THE REGULATORY MECHANISM THAT MAY RESTRAIN GB IN ITS PREFUSION FORM. THE PROPOSAL IS INNOVATIVE BECAUSE, TO OUR KNOWLEDGE, THIS IS THE FIRST TIME THE SOLUBLE PREFUSION FORM OF HCMV GB WAS SUCCESSFULLY ENGINEERED. THE PROPOSAL IS SIGNIFICANT BECAUSE IT WILL YIELD NEW MECHANISTIC KNOWLEDGE AND PROVIDE NEW REAGENTS THAT COULD AID IN THE DEVELOPMENT OF OPTIMAL VACCINES AND PASSIVE IMMUNIZATION STRATEGIES AGAINST HCMV.

ISOLATION OF EARLY SPORULATION GENES

ASTROLGLIA-MEDIATED PATHOGENIC MECHANISMS IN FRAGILE X SYNDROME (FXS)

OPTIMIZING INTEGRATION OF VETERINARY CLINICAL RESEARCH FINDINGS WITH HUMAN HEALTH SYSTEMS TO IMPROVE STRATEGIES FOR EARLY DETECTION AND INTERVENTION - PROJECT SUMMARY EXPERIMENTALLY INDUCED ANIMAL MODELS OF DISEASE PLAY A CRITICAL ROLE IN THE DEVELOPMENT, EVALUATION AND OPTIMIZATION OF THERAPEUTICS FOR HUMAN DISEASE. WITH THE ADVENT OF GENETIC ENGINEERING, SUCH MODEL SYSTEMS HAVE SUBSTANTIALLY IMPROVED; HOWEVER, TRANSLATIONAL FAILURE RATES REMAIN HIGH FOR MOST DISEASE ENTITIES. ONE PROMISING APPROACH INVOLVES USING PET DOGS WITH SPONTANEOUS DISEASE TO EVALUATE TREATMENT STRATEGIES FOR DISEASES SUCH AS CANCER, HEART FAILURE AND NEURODEGENERATION PRIOR TO HUMAN TRIALS, WITH THE GOAL OF IMPROVING CLINICAL OUTCOMES. BEYOND THEIR INHERENT BIOLOGICAL RELEVANCE, TRANSLATIONAL ADVANTAGES OF THIS MODEL INCLUDE LONGITUDINAL ASSESSMENT OF INDIVIDUAL PATIENTS USING DIAGNOSTICS AND INTERVENTIONS THAT PARALLEL HUMAN PROCESSES, COMPRESSED DISEASE TIMELINES THAT PERMIT RAPID EVALUATION OF THERAPEUTIC IMPACT, AND THE FREEDOM TO STUDY UNIQUE TREATMENT COMBINATIONS IN LIEU OF STANDARDS OF CARE. AS HUMAN MEDICINE PROGRESSIVELY ADOPTS STRATEGIES DESIGNED TO PREVENT DISEASE PROGRESSION THROUGH EARLY DETECTION AND INTERVENTION, STUDIES IN PET DOGS HAVE THE POTENTIAL TO CONTRIBUTE VALUABLE PRECLINICAL INFORMATION. SEVERAL RESOURCES NOW SUPPORT SUCH WORK INCLUDING THE NCI INTEGRATED CANINE DATA COMMONS, SMART IACUC FOR MULTI-SITE STUDIES, THE CTSA ONE HEALTH ALLIANCE AND A MARKEDLY IMPROVED CANINE REFERENCE GENOME (CANFAM4) AND ASSOCIATED KEY OMICS TOOLS. DESPITE THESE ADVANCES, EFFECTIVE ALIGNMENT AND INTEGRATION OF DATA GENERATED FROM PET DOGS WITH HUMAN HEALTH SYSTEMS REMAINS A SUBSTANTIAL CHALLENGE. TO BEGIN ADDRESSING THIS GAP, WE DEVELOPED A VETERINARY DATA MODEL THAT IS HARMONIZED WITH THE OBSERVATIONAL MEDICAL OUTCOMES PARTNERSHIP COMMON DATA MODEL (OMOPV5+ CDM) AND GENERATED TOOLS FOR CORE RESEARCH INFRASTRUCTURE INCLUDING, TRANSLATOR (TRANSLATIONAL ANIMAL SHARED COLLABORATIVE OBSERVATIONAL RESEARCH). IN THE CURRENT APPLICATION, WE WILL BUILD UPON OUR PRIOR WORK AND USE PET DOGS TO DEVELOP, VALIDATE, AND OPTIMIZE TOOLS FOR EARLY DISEASE DETECTION, AND IN PARALLEL, RESOURCE THESE STUDIES TO ITERATIVELY ADVANCE METHODOLOGIES FOR IMPROVING CONNECTIVITY AND APPLICATION OF SUCH DATA SETS TO HUMAN HEALTH PROCESSES. TO ACCOMPLISH THIS, WE WILL 1) CREDENTIAL A LIQUID BIOPSY ASSAY FOR EARLY DETECTION OF CANCER RELAPSE IN PET DOGS AND RAPIDLY TEST INNOVATIVE STRATEGIES TO PREVENT PROGRESSION; 2) VALIDATE AN INTEGRATED ULTRASOUND/EXOSOME DIAGNOSTIC FOR EARLY DETECTION OF CARDIAC CACHEXIA IN PET DOGS AND ASSESS NOVEL APPROACHES TO HALT WASTING; AND 3) FURTHER ENHANCE THE UTILITY OF OUR OMOPV5+ CDM AND RELATED INFORMATICS TOOLS TO REALIZE THE TRANSLATIONAL POTENTIAL OF PET DOG TRIALS. AN OUTSTANDING TEAM BLENDING HUMAN AND VETERINARY MEDICINE, COMPARATIVE GENOMICS, BIOMEDICAL ENGINEERING, RESEARCH INFORMATICS INFRASTRUCTURE AND PRECLINICAL TRANSLATIONAL MODELING, SUPPORTED BY AN ADVISORY PANEL OF HUMAN HEALTH EXPERTS, WILL FACILITATE SUCCESSFUL COMPLETION OF STATED MILESTONES. IMPORTANTLY, THE PROPOSED WORK INTEGRATES WITH AND IS SUPPORTED BY THE PARENT UM1, ENSURING THAT SCIENTIFIC ADVANCEMENTS FOR EARLY DISEASE DETECTION AND INTERVENTION CO-EVOLVE WITH METHODOLOGIES THAT IMPROVE FUNDAMENTAL PROCESSES NECESSARY FOR INTERPRETATION AND FUTURE UTILITY OF THE SCIENCE.

THE INTERFACE BETWEEN L. PNEUMOPHILA MANIPULATION OF HOST ENDOPLASMIC RETICULUM AND INNATE IMMUNE SUBTERFUGE

COPING WITH STRESS: NEXT GENERATION APPROACHES TO BORRELIA BURGDORFERI HOST ADAPTATION

MICROBIAL DETERMINANTS OF EXCESSIVE INFLAMMATION AND SEVERE LYME DISEASE - PROJECT SUMMARY/ABSTRACT LYME DISEASE HAS REACHED EPIDEMIC PROPORTIONS IN SEVERAL REGIONS IN UNITED STATES AND EUROPE AND POSES A SUBSTANTIAL BURDEN ON AFFECTED COMMUNITIES. THE ILLNESS ENCOMPASSES A SPECTRUM OF CLINICAL MANIFESTATIONS WHICH VARY IN SEVERITY AND DURATION, INCLUDING COMPLICATIONS THAT PERSIST AFTER ANTIBIOTIC-THERAPY, TERMED POST- LYME SYNDROMES. HOWEVER, THE REASONS FOR THIS RANGE IN DISEASE SEVERITY ARE NOT CLEAR AND BIOMARKERS TO IDENTIFY PATIENTS AT GREATER RISK FOR ADVERSE OUTCOMES ARE LACKING. OUR FINDINGS SUGGEST THAT INAPPROPRIATE IMMUNE RESPONSES, WHICH ARE SHAPED BY MICROBIAL AND HOST GENETICS, ARE AN IMPORTANT FACTOR IN DISEASE SEVERITY. WE PREVIOUSLY IDENTIFIED A PARTICULARLY VIRULENT BORRELIA BURGDORFERI (BB) RST1 STRAIN WHICH LEADS TO EXCESSIVE INFLAMMATION AND SEVERE DISEASE, INCLUDING HIGHLY SYMPTOMATIC EARLY INFECTION AND A GREATER RISK FOR ANTIBIOTIC-REFRACTORY LYME ARTHRITIS, A POST-LYME COMPLICATION OF THIS DISEASE. THESE FINDINGS PROVIDED A NEW PARADIGM FOR STUDYING MICROBIAL UNDERPININGS OF MALADAPTIVE IMMUNITY AND UNTOWARD CLINICAL OUTCOMES IN LYME DISEASE. HOWEVER, BB COMPONENTS RESPONSIBLE FOR EXCESSIVE INFLAMMATION AND SEVERE DISEASE ARE NOT KNOWN. SEVERAL LINES OF EVIDENCE POINT TO DIFFERENCES IN EXPRESSION OR SEQUENCE VARIATION IN BORRELIA LIPOPROTEINS AS A MAJOR DETERMINANT OF THESE OUTCOMES. IN THIS PROPOSAL, WE ARE LEVERAGING OUR UNIQUE COLLECTION OF CLINICAL SAMPLES FROM WELL-DEFINED PATIENTS, AND FUNCTIONAL STUDIES USING GENETICALLY-ENGINEERED ISOGENIC BB STRAINS TO SYSTEMATICALLY DELINEATE THE IMMUNOGENIC LIPOPROTEINS AND ASCERTAIN THEIR FUNCTION IN DYSREGULATED IMMUNE RESPONSES AND ADVERSE CLINICAL OUTCOMES IN LYME DISEASE. WE PROPOSE TO: AIM 1. DETERMINE THE INFLAMMATORY CAPACITY OF CANDIDATE LIPOPROTEINS ARP OR OSPC IN VITRO BY GENERATING STRAINS CONTAINING ARP OR OSPC VARIANTS AND TESTING THEIR INFLAMMATORY CAPACITY IN HUMAN PBMC CULTURES. AIM 2. DELINEATE THE IMPACT OF ARP AND OSPC-A EXPRESSING STRAINS ON ARTHRITIS SEVERITY IN MICE BY TESTING EARLY AND LATE IMMUNE RESPONSES AND ARTHRITIS SEVERITY IN C3H MICE INFECTED WITH ISOGENIC STRAINS EXPRESSING ARP OR OSPC VARIANTS, AND ASCERTAIN THE IMPACT OF ARP AND OSPC ON IMMUNE RESPONSE AND DISEASE SEVERITY IN PATIENTS BY CHARACTERIZING EARLY AND LATE IMMUNE RESPONSES IN PATIENTS WITH PTLDS, DEFINING THE IMPACT OF ARP & OSPC ON THESE IMMUNE RESPONSES AND, IDENTIFYING NEW BB DETERMINANTS OF IMMUNOGENICITY AND VIRULENCE USING GWAS WITH IMMUNE AND CLINICAL PHENOTYPE IN PATIENTS. THESE STUDIES WILL GENERATE NEW INSIGHTS INTO PATHOGENESIS OF LYME DISEASE AND MAY HELP LAY THE GROUNDWORK FOR NOVEL DIAGNOSTIC APPROACHES TO IDENTIFY PATIENTS AT GREATER RISK FOR SEVERE DISEASE. THE ABILITY TO IDENTIFY SUCH PATIENTS COULD HELP GUIDE MORE EFFECTIVE TREATMENT STRATEGIES WHICH INCORPORATE IMMUNOMODULATORY THERAPIES TO QUIET THE IMMUNE RESPONSE; AN APPROACH THAT IS ALREADY EMPLOYED FOR TREATMENT OF PATIENTS WITH REFRACTORY LYME ARTHRITIS.

ELECTROTHERAPEUTIC STRATEGIES FOR CONNECTIVE TISSUE REPAIR

INTEGRATING ENGINEERING & LITERACY

HIGH ENERGY PHYSICS AT TUFTS UNIVERSITY

NEUROPEPTIDES, SOCIAL STRESS AND DRUGS OF ABUSE

WNT7A-MEDIATED COMPETENCE TO RESIST OSTEOARTHRITIS PROGRESSION - ABSTRACT: WNT7A-MEDIATED COMPETENCE TO RESIST OSTEOARTHRITIS PROGRESSION OSTEOARTHRITIS (OA) IS A HIGHLY PREVALENT AND DEBILITATING DISEASE THAT CURRENTLY HAS NO EFFECTIVE THERAPY. OA HAS MANY RISK FACTORS, SUCH AS JOINT INJURY AND AGING. HOWEVER, MANY PEOPLE WITH THESE RISK FACTORS DO NOT DEVELOP OA OR DEVELOP IT TO A LESSER EXTENT. INDIVIDUAL RESPONSES TO THE SAME TREATMENT ARE OFTEN ALSO HIGHLY VARIABLE, HAMPERING THE TESTING OF THERAPY IN A REASONABLE-SIZED POPULATION. THUS, THERE IS AN URGENT NEED TO UNDERSTAND THE BASIS FOR THE DIVERSE MANIFESTATIONS OF OA. ONE DRIVING FACTOR OF OA IS PROPOSED TO BE LOCAL INFLAMMATION. AS PROLONGED INFLAMMATION ELICITS CATABOLIC CHANGES IN THE JOINT, THE ABILITY OF EACH INDIVIDUAL TO RESIST INFLAMMATION COULD BE DIRECTLY LINKED TO THE TRAJECTORY OF DISEASE PROGRESSION. IDENTIFYING FACTORS THAT PROVIDE THE COMPETENCE TO RESIST INFLAMMATION MAY BE KEY TO ELUCIDATING THE CAUSE OF OA PROGRESSION IN INDIVIDUALS. OUR LONG-TERM GOAL IS TO INVESTIGATE OA PATHOGENESIS TO IMPROVE ITS TREATMENT. THE GOAL OF THIS GRANT IS TO INVESTIGATE THE COMPETENCE TO RESIST INFLAMMATION AND JOINT DESTRUCTION CONFERRED BY AN UNDEREXPLORED MOLECULE (WNT7A) FROM THE WNT SIGNALING FAMILY. THIS PROPOSAL IS BASED ON OUR STUDY THAT SHOWED A STRIKING NEGATIVE-EXPONENTIAL RELATIONSHIP BETWEEN WNT7A AND CATABOLIC GENES IN INDIVIDUAL HUMAN CARTILAGE SPECIMENS. WHEN WNT7A EXPRESSION WAS BELOW A CERTAIN THRESHOLD, THE SAMPLES WERE ALMOST ALWAYS OF OA BACKGROUND, AS IF LOW LEVELS OF WNT7A SIGNIFY A HIGHER RISK OF OA. IN THIS WAY, WNT7A MAY BE A KEY FACTOR ASSOCIATED WITH OA VARIABILITY. ECTOPIC EXPRESSION OF WNT7A UNDER NORMAL CONDITIONS DID NOT IMPACT CARTILAGE MATRIX LEVELS, BUT STRONGLY HALTED JOINT DESTRUCTION IN EXPERIMENTAL OA, SUGGESTING THAT WNT7A PROVIDED THE JOINT WITH A CERTAIN ABILITY TO RESIST OA. THUS, WE HYPOTHESIZE THAT THE LEVEL OF WNT7A WITHIN ARTICULAR CARTILAGE DETERMINES THE COMPETENCE AGAINST INFLAMMATION AND IMPACTS THE TRAJECTORY OF OA IN EACH INDIVIDUAL, FORMING THE BASIS FOR OA VARIABILITY. THIS HYPOTHESIS WILL BE TESTED IN TWO SPECIFIC AIMS BY 1) INVESTIGATING WHETHER WNT7A ALTERS THE COURSE OF INFLAMMATION AND THE TRAJECTORY OF CARTILAGE LOSS AND JOINT DESTRUCTION IN OA AND 2) IDENTIFYING DOWNSTREAM PATHWAYS AND UPSTREAM REGULATORS OF WNT7A. WE WILL USE GAIN- AND LOSS-OF FUNCTION APPROACHES ON MOUSE OA AND HUMAN CARTILAGE SPECIMENS. THE NOVELTY OF THIS STUDY LIES IN THE CONCEPT OF WNT7A AS A COMPETENCE FACTOR FOR OA RESISTANCE IN INDIVIDUALS TO EXPLORE THE MECHANISM OF HETEROGENEITY IN OA, AND IN THE USE OF ADVANCED IMAGING TECHNOLOGIES TO TEST THESE CONCEPTS. THESE STUDIES WILL DEFINE THE ROLE OF WNT7A IN CURTAILING PROLONGED INFLAMMATION AND THE PROPENSITY FOR DEGENERATIVE CHANGES IN OA. FURTHERMORE, IT WILL IDENTIFY FUNDAMENTAL MECHANISMS FOR ENHANCING OR PRESERVING ENDOGENOUS WNT7A FUNCTION IN CARTILAGE FOR JOINT PROTECTION. THUS, THIS WORK WILL PROVIDE IMPORTANT MECHANISTIC INSIGHTS INTO OA PROGRESSION AND ITS VARIABILITY AND THE DESIGN OF STRATEGIES TO TREAT THIS DISEASE.

MECHANISMS OF NUCLEAR EGRESS IN HERPESVIRUSES - PROJECT SUMMARY/ABSTRACT HERPESVIRUSES USE AN UNUSUAL PATHWAY TO EXPORT THEIR CAPSIDS FROM THE NUCLEUS WHERE THEY ARE FORMED INTO THE CYTOPLASM WHERE THEY MATURE INTO INFECTIOUS VIRIONS. INSTEAD OF USING THE CANONICAL ROUTE THROUGH THE NUCLEAR PORE, CAPSIDS UNDERGO BUDDING AT THE INNER NUCLEAR MEMBRANE TO FORM PERINUCLEAR ENVELOPED VIRIONS THAT SUBSEQUENTLY FUSE WITH THE OUTER NUCLEAR MEMBRANE, RELEASING THE CAPSIDS INTO THE CYTOPLASM. THE NUCLEAR EGRESS COMPLEX (NEC), COMPOSED OF TWO VIRALLY ENCODED PROTEINS, IS THE KEY PLAYER IN THE MEMBRANE BUDDING STAGE OF THIS PROCESS. PREVIOUSLY, WE DISCOVERED THAT THE NEC FROM THE PROTOTYPICAL A-HERPESVIRUS, HERPES SIMPLEX VIRUS 1, IS A COMPLETE VIRALLY ENCODED MEMBRANE-BUDDING MACHINE, THE ONLY ONE CURRENTLY KNOWN TO MEDIATE BUDDING OF THE NUCLEAR, AS OPPOSED TO CYTOPLASMIC, MEMBRANES. WE ALSO SHOWED THAT THE NEC DEFORMS AND BUDS MEMBRANES BY USING A DUAL MECHANISM, IN WHICH MEMBRANE CURVATURE IS GENERATED BOTH LOCALLY (BY PERIPHERAL MEMBRANE INSERTION) AND GLOBALLY (BY THE FORMATION OF A CURVED OLIGOMERIC SCAFFOLD). IN ADDITION, WE HAVE DETERMINED THE HIGH-RESOLUTION STRUCTURES OF SEVERAL NEC HOMOLOGS THAT ARE NOW USED TO GUIDE FUNCTIONAL STUDIES. THESE RESULTS HAVE TRANSFORMED OUR UNDERSTANDING OF HOW HERPESVIRUSES MANIPULATE HOST MEMBRANES. THE CURRENT APPLICATION BUILDS LOGICALLY ON THESE AND OTHER RECENT ACHIEVEMENTS AND WILL LEVERAGE THE COMBINED POWER OF STRUCTURAL AND FUNCTIONAL APPROACHES TO FILL IN THE CRITICAL GAPS IN OUR UNDERSTANDING OF BOTH BUDDING AND FUSION STAGES OF NUCLEAR EGRESS. AIM 1 WILL EXPAND THE MECHANISTIC AND STRUCTURAL STUDIES OF THE NEC TO HOMOLOGS FROM THE DISTANTLY RELATED G-HERPESVIRUSES. AIM 2 WILL VISUALIZE THE NUCLEAR EGRESS PROCESS IN INFECTED CELLS IN SITU AT A HIGH RESOLUTION USING CRYOELECTRON TOMOGRAPHY. AIM 3 WILL CHARACTERIZE A NEW HOST FACTOR PROMOTING FUSION DURING NUCLEAR EGRESS. OUR PRIOR STUDIES MADE IMPORTANT CONTRIBUTIONS TO THE CURRENT KNOWLEDGE OF HOW HERPESVIRUS CAPSIDS BUD AT THE NUCLEAR ENVELOPE. WE ANTICIPATE THAT UPON SUCCESSFUL COMPLETION, THE PROPOSED WORK WILL UNCOVER NEW MECHANISMS AND GENERATE NEW MODELS, THEREBY TRANSFORMING OUR UNDERSTANDING OF NUCLEAR EGRESS.

NANOSTRUCTURED, METAL-ION MODIFIED CERIA AND ZIRCONIA OXIDATION CATALYSTS

A VERSATILE STRUCTURE-BASED THERAPEUTIC PLATFORM FOR DEVELOPMENT OF VHH-BASED ANTITOXIN AND ANTIVIRAL AGENTS - ABSTRACT IN PREVIOUS NIH SPONSORED RESEARCH WE SUCCESSFULLY TESTED THE HYPOTHESIS THAT INTEGRATING STRUCTURAL AND MECHANISTIC INFORMATION INTO HETEROMULTIMERIC VHH-BASED NEUTRALIZING AGENT (VNA) DESIGN FACILITATED DEVELOPMENT OF ANTITOXINS WITH EVEN GREATER EFFICACY AND VERSATILITY. IN THIS RENEWAL PROPOSAL, WE WILL APPLY THESE FINDINGS TO TEST THE HYPOTHESIS THAT OUR DESIGNER VNA PLATFORM, WHICH IS RAPIDLY RESPONSIVE TO NEW THREATS, WILL PERMIT DEVELOPMENT OF HIGHLY PRACTICAL, NEXT-GENERATION ANTITOXIN AND ANTIVIRAL PRODUCTS THAT POSSESS EXCELLENT POTENCIES IN TREATING INTOXICATIONS OR VIRAL INFECTIONS AND ARE EFFECTIVE AGAINST A BROAD RANGE OF NATURAL PATHOGEN VARIANTS. OUR RESEARCH WILL FOCUS ON TWO PATHOGENS THAT ARE MAJOR CURRENT THREATS WHICH COULD BENEFIT FROM NEXT- GENERATION THERAPEUTICS: BOTULINUM NEUROTOXIN (BONT) AND SARS-COV-2. WE PROPOSE TWO SPECIFIC AIMS WHICH WILL BE UNDERWAY SIMULTANEOUSLY THROUGHOUT THE FIVE YEARS OF RESEARCH. IN AIM 1, WE WILL DEVELOP A SMALL POOL OF ANTITOXIN VNAS THAT PROTECT AGAINST ALL SUBTYPES OF THE THREE PREVALENT BONT SEROTYPES (A, B AND E). BONTS ARE CDC TIER 1 SELECT AGENTS. HOWEVER, THE FEW AVAILABLE ANTITOXIN TREATMENTS AGAINST BONTS PRIMARILY DERIVE FROM LARGE ANIMAL POLYCLONAL ANTISERA, SUCH AS THE EQUINE BOTULISM ANTITOXIN HBAT, WHICH SUFFER FROM MULTIPLE MANUFACTURING AND STORAGE CHALLENGES. OUR GOAL IS TO TEST THE PLATFORM’S ABILITY TO PRODUCE HIGHLY PRACTICAL VNAS AS A NEXT-GENERATION BONT ANTITOXIN PRODUCT, LIKELY DELIVERED AS RNA NANOPARTICLES, WHICH IMPROVES ON THE POTENCIES AND NATURAL VARIANT SPECIFICITIES OF THE CURRENT HBAT ANTITOXIN PRODUCT AND IS RAPIDLY RESPONSIVE TO POTENTIAL NEW BONT THREATS. IN AIM 2 WE WILL DEVELOP A SINGLE VNA ANTIVIRAL AGENT THAT PROTECTS AGAINST KNOWN VARIANTS OF SARS-COV-1 AND SARS-COV-2. SARS-COV-2 IS THE VIRAL CAUSE OF THE ONGOING COVID-19 PANDEMIC. A PROMISING STRATEGY FOR RAPID DEVELOPMENT OF A THERAPY IS DEVELOPMENT OF SARS-COV-2 NEUTRALIZING ANTIBODIES, ESPECIALLY ANTIBODIES TARGETING THE SPIKE PROTEIN, FOR PROPHYLACTIC OR PASSIVE IMMUNOTHERAPIES. HOWEVER, NOVEL VARIANTS OF SARS-COV-2, WHICH CAUSE ENHANCED INFECTION AND TRANSMISSION, HAVE EMERGED, AND MORE DANGEROUS VARIANTS ARE EXPECTED TO EVOLVE. OF IMMEDIATE CONCERN ARE VARIANTS THAT PARTIALLY ESCAPE NEUTRALIZATION BY CURRENT AB-BASED THERAPIES AND IN VACCINATED OR PREVIOUSLY-INFECTED COVID-19 PATIENTS, LEADING TO REDUCED VACCINE EFFICACY IN CERTAIN AREAS WITH A HIGH PREVALENCE OF THESE VARIANTS. WE PROPOSE AN MRNA- BASED ANTIVIRAL PRODUCT THAT, ONCE ADMINISTERED, ELICITS EXPRESSION OF A VNA WITH EXTREMELY HIGH VIRUS NEUTRALIZING POTENCY. THE VNA WILL CONTAIN MULTIPLE COVALENTLY LINKED VHHS BINDING TO CONSERVED EPITOPES OF THE SPIKE PROTEIN. THIS APPROACH WILL TEST THE PLATFORM’S ABILITY TO DEVELOP A PRODUCT THAT MINIMIZES THE RISKS OF IMMUNE ESCAPE THROUGH EVOLUTION AND SELECTION OF CLINICAL STRAINS OF SARS-COV-2 AND SARS-COV-1. IF SUCCESSFUL, THIS TECHNOLOGY PLATFORM COULD HAVE BROAD APPLICATIONS IN CREATING PRACTICAL THERAPEUTICS FOR A WIDE VARIETY OF EMERGING AND POTENTIAL PANDEMIC VIRAL INFECTIONS, BIOTERROR THREAT AGENTS, AND OTHER INFECTIOUS DISEASES.

TISSUE REGENERATION BY BIOPHYSICAL SIGNALING

REGULATION OF NEUROGENESIS IN OLFACTORY EPITHELIUM

IMPACT OF VITAMIN D SUPPLEMENTATION ON CARDIOMETABOLIC RISK IN SCHOOLCHILDREN

IGERT: WATER ACROSS BOUNDARIES - INTEGRATION OF SCIENCE ENGINEERING AND DIPLOMACY

PROBE-BASED TWO PHOTON MICROSCOPY FOR FUNCTIONAL, LABEL-FREE EARLY CANCER DIAGNOSIS

INVESTIGATION OF YOP ACTIVITIES IN M CELLS DURING MURINE INFECTION - PROJECT ABSTRACT MICROFOLD (M) CELLS ARE SPECIALIZED CELLS IN THE GASTROINTESTINAL (GI) EPITHELIUM. THEY ARE IMPORTANT SENTINEL CELLS OF THE GUT-ASSOCIATED LYMPHOID TISSUE (GALT), BECAUSE THEY DELIVER FOREIGN ANTIGENS AND PARTICLES TO THE IMMUNE CELLS THAT UNDERLIE THE INTESTINAL EPITHELIUM. THEIR SPECIALIZED FUNCTION IS FACILITATED BOTH BY NUMEROUS RECEPTORS ON THEIR APICAL SURFACE THAT BIND TO ANTIGENS AND THEIR ABILITY TO RAPIDLY TRANSCYTOSE BOUND ANTIGENS TO THE PEYER’S PATCHES. IN THEIR ABSENCE, IMMUNE RESPONSES ARE MUTED. HOWEVER, M CELLS ARE ALSO EXPLOITED BY MANY ENTERIC BACTERIAL AND VIRAL PATHOGENS AS CELLULAR PORTALS THAT PERMIT THE PATHOGENS TO GAIN ACCESS TO THE LYMPH SYSTEM AND DEEPER TISSUES. STUDY M CELLS HAS BEEN CHALLENGING BECAUSE THEY ARE A MINOR FRACTION OF THE GUT EPITHELIUM, ARE TERMINALLY DIFFERENTIATED, AND UNTIL RECENTLY, COULD NOT BE GROWN IN CULTURE. WE ESTABLISHED A DIFFERENTIATED HUMAN ILEUM ORGANOID MODEL SYSTEM USING TRANSWELLS. THIS ALLOWS US TO INDUCE M CELL DEVELOPMENT SIMULTANEOUSLY WITH OTHER MAJOR AND MINOR EPITHELIAL CELL TYPES AND FORM A POLARIZED MODEL ILEAL MONOLAYER. INFECTION OF THESE MODEL INTESTINAL SYSTEMS WITH THE ENTERIC PATHOGEN, YERSINIA PSEUDOTUBERCULOSIS (YPTB) REVEALED THAT YPTB BOUND EXTENSIVELY TO THE APICAL SURFACE OF M CELLS, AND MINIMALLY TO OTHER CELL TYPES, USING ITS ADHESIN, INVASIN. YPTB CARRIES A TYPE 3 SECRETION SYSTEM (T3SS) THAT IS EXPRESSED AT 37°C, INJECTS EFFECTOR PROTEINS CALLED YOPS INTO HOST CELLS AND IS ESSENTIAL FOR YPTB SURVIVAL IN THE GI TRACT AND PEYER’S PATCHES. YPTB EXPRESSING THE T3SS REMAINED BOUND EXTRACELLULARLY TO THE APICAL SURFACE OF M CELLS IN THESE MONOLAYERS. BY CONTRAST, YPTB WAS INTERNALIZED AND DELIVERED 20 TIMES MORE EFFICIENTLY TO THE BASOLATERAL SIDE IN THE ABSENCE OF THE T3SS. THE COMBINED ACTIVITIES OF THE TRANSLOCATED EFFECTORS, YOPE, A GTPASE ACTIVATING PROTEIN (GAP) THAT INACTIVATES RAC1, RHOG AND RHOA, AND YOPH, A TYROSINE PHOSPHATASE, PREVENTED INTERNALIZATION. STRIKINGLY, YOPE CAUSED EXTRUSION OF M CELL FROM THE MONOLAYER BY AN UNKNOWN MECHANISM. THESE RESULTS DEMONSTRATE A PRONOUNCED IMPACT OF YPTB INFECTION ON M CELLS AND PROVOKE THE HYPOTHESIS THAT YPTB INFECTION OF M CELLS INDUCES M CELL DEPLETION, AND THAT THE LOSS OF THIS COMPONENT OF THE MUCOSAL IMMUNE SYSTEM PROFOUNDLY IMPACTS RESPONSES TO SUBSEQUENT IMMUNE CHALLENGE AND INFECTION. TO TEST THIS HYPOTHESIS AND GAIN INSIGHTS INTO M CELL FUNCTIONS AT A MOLECULAR MECHANISTIC LEVEL, WE ARE PROPOSING THE FOLLOWING TWO AIMS: (1) DETERMINE HOW INFECTION WITH YPTB IMPACTS M CELL ABUNDANCE AND FUNCTION IN THE PEYER’S PATCHES AND IN PYOGRANULOMA AREAS IN THE GI TRACT: AND (2) EVALUATE THE ROLES OF YOP TARGETS IN M CELL ACTIVITIES, INCLUDING M CELL EXTRUSION, PARTICLE INTERNALIZATION AND TRANSCYTOSIS. THESE STUDIES WILL DEFINE HOW INFECTION WITH AN ENTERIC PATHOGEN ALTERS M CELL PHYSIOLOGY AND FUNCTIONS DURING AND AFTER INFECTION.

NUTRITION RESEARCH FOR HEALTHY AGING AND PREVENTION OF CHRONIC DISEASE

AGE-RELATED OLFACTORY LOSS: MECHANISMS AND TREATMENT OPTIONS

MECHANISMS OF T CELL ACTIVATION IN CARDIAC FIBROSIS AND NON-ISCHEMIC HEART FAILURE

REDUCING RACIAL DISPARITIES IN SMM POST COVID19: ASSESSING THE INTEGRATION OF MATERNAL SAFETY BUNDLES AND COMMUNITY BASED DOULAS TO IMPROVE OUTCOMES FOR BLACK WOMEN

MULTIPLE B. BURGDORFERI FACTORS COLLABORATE TO EVADE COMPLEMENT-MEDIATED DEFENSES

ENHANCING THE EFFICACY OF IMMUNOTHERAPY IN DLBCL USING RATIONAL COMBINATION APPROACHES

REPLICATION OF SIMPLE DNA REPEATS

NONINVASIVE BLADDER CANCER DIAGNOSTICS VIA MACHINE LEARNING ANALYSIS OF NANOSCALE SURFACE IMAGES OF EPITHELIAL CELLS EXTRACTED FROM VOIDED URINE SAMPLES - PROJECT SUMMARY/ABSTRACT BLADDER CANCER IS COMMON CANCER WITH AN ESTIMATED 81,190 NEW CASES AND 17,240 DEATHS IN 2018 (WITH > 500,000 SURVIVORS) ONLY IN THE US. THE GOLD STANDARD FOR DIAGNOSIS OF BLADDER CANCER INCLUDES AN INVASIVE OPTICAL BLADDER EXAMINATION (CYSTOSCOPY) AND TUMOR RESECTION FOR PATHOLOGY EXAMINATION. BECAUSE OF A HIGH RECURRENCE RATE OF THIS CANCER (50-80%), FREQUENT (ONCE EVERY 3-6-12 MONTHS) COSTLY AND INVASIVE CYSTOSCOPY EXAMS ARE REQUIRED TO MONITOR PATIENTS FOR RECURRENCE AND/OR PROGRESSION TO A MORE ADVANCED STAGE. IT MAKES BLADDER CANCER THE MOST EXPENSIVE CANCER TO MONITOR/FOLLOW UP AND TREAT PER PATIENT. MOREOVER, THE INVASIVE NATURE OF THE CURRENT STANDARD OF CARE, CYSTOSCOPY, CAUSES RATHER LOW COMPLIANCE OF PATIENT TO FOLLOW THIS PROCEDURE. THERE IS AN URGENT UNMET NEED FOR A BLADDER CANCER SCREENING AND MONITORING TEST, WHICH WILL BE NONINVASIVE, RAPID, OBJECTIVE, REPRODUCIBLE, EASY TO PERFORM AND INTERPRET, AND HIGHLY ACCURATE. SUCH A TEST WILL REDUCE THE NEED IN FREQUENT CYSTOSCOPIES AND GREATLY EXPAND THE PARTICIPATION OF PATIENTS IN SCREENING AND EARLY DETECTION PROGRAMS BECAUSE IT DECREASES THE PATIENT DISCOMFORT AND POST-PROCEDURAL COMPLICATIONS. HERE WE PROPOSE TO DEVELOP SUCH A TEST FOR IDENTIFICATION OF THE PRESENCE OF BLADDER CANCER AND ITS AGGRESSIVENESS (GRADE). IT WILL BE BASED ON NON-INVASIVE ANALYSIS OF INDIVIDUAL CELLS EXTRACTED FROM URINE (EXTRACTION TECHNOLOGY ALREADY EXISTS IN HOSPITALS FOR VOIDED URINE CYTOLOGY TESTS, (VUC) THE CURRENT STANDARD-OF- CARE, A NON-INVASIVE EXAMINATION OF CELLS IN URINE USED TO ASSIST WITH CANCER DIAGNOSIS AND SURVEILLANCE). A NOVEL MODALITY OF ATOMIC FORCE MICROSCOPY (AFM) WILL BE USED FOR NANOSCALE IMAGING OF CELLS EXTRACTED FROM URINE, MAPPING/IMAGING OF THE PHYSICAL PROPERTIES OF THE CELL SURFACE. THE COLLECTED IMAGES WILL FURTHER BE ANALYZED USING MACHINE-LEARNING METHODS AND NOVEL ADVANCED STATISTICAL APPROACHES TO IDENTIFY A “DIGITAL SIGNATURE” OF CANCER. THE PROPOSED TECHNOLOGY IS FUNDAMENTALLY DIFFERENT FROM PREVIOUSLY STUDIED URINE BIOMARKERS AND ALL EXISTING PHYSICAL METHODS BECAUSE IT IS BASED ON THE ANALYSIS OF PHYSICAL PROPERTIES OF THE CELL SURFACE, NOT CELL BULK OR PRESENCE OF BIOCHEMICAL MARKERS OR GENETIC ANALYSIS. OUR STRONG PRELIMINARY RESULTS DEMONSTRATE THE FEASIBILITY OF THE PROPOSED APPROACH, ITS PRESUMED SUPERIORITY COMPARED TO THE CURRENTLY USED NON-INVASIVE METHODS, AND LEAD US TO THE CENTRAL HYPOTHESIS THAT BLADDER CANCER CAN BE IDENTIFIED BY ANALYZING A SMALL NUMBER OF CELLS RANDOMLY CHOSEN FROM URINE SAMPLES, WITH A LOW SAMPLING ERROR. THIS IS A SUBSTANTIAL DEPARTURE FROM VUC TESTS, WHICH REQUIRE A VISUAL ANALYSIS OF MANY CELLS. SUPPORTED BY THE PRELIMINARY DATA, WE PROPOSE (1) TO OPTIMIZE AND EXPAND THE METHOD, (2) TO DEFINE THE ACCURACY OF CANCER DETECTION ON A LARGE COHORT OF PATIENTS, AND (3) TO ASSESS THE ACCURACY OF IDENTIFICATION OF AGGRESSIVENESS (LOW VERSUS HIGH GRADE) OF BLADDER CANCER. OUR LONG-TERM GOAL IS TO DEVELOP A NON-INVASIVE CLINICAL METHOD FOR ACCURATE DETECTING OF PRESENCE AND MONITORING BLADDER CANCER AS WELL AS MANY OTHER CANCERS, IN WHICH CELLS CAN BE EXTRACTED FROM EASILY ACCESSIBLE BODILY FLUIDS WITHOUT THE NEED FOR TISSUE BIOPSY (E.G URINE-BLADDER & UPPER URINARY TRACT CANCER, STOOL- COLORECTAL CANCER, SPUTUM-AERODIGESTIVE CANCER, CERVICAL SMEARS-CERVICAL CANCER ETC.), USING METHODS BASED ON THE ANALYSIS OF PHYSICAL CHARACTERISTICS OF THE CELL SURFACE. THE PROPOSED RESEARCH, WHICH IS THE FIRST STEP IN PURSUIT OF THIS OVERARCHING GOAL.

HOSPITAL AND HOUSEHOLD STUDIES OF RESPIRATORY CRYPTOSPORIDIOSIS AND TRANSMISSION

BACE1 TRAFFICKING AND DEGRADATION IN ALZHEIMER?S DISEASE

ROLE OF C-DIGMP SIGNALING IN VIBRIO CHOLERAE VIRULENCE

THE YEAST SURFACE AS A PLATFORM FOR INHIBITOR DISCOVERY

MICROBIAL DISRUPTION OF DENDRITIC CELL MATURATION AND FUNCTION

BIOPHYSICAL AND STRUCTURAL ANALYSIS OF THE HERPESVIRAL NUCLEAR BUDDING MACHINERY

PROTEOLYTIC REGULATION OF SPORE GERMINATION IN CLOSTRIDIUM DIFFICILE

STIMULUS-SECRETION COUPLING IN DISEASED LACRIMAL GLAND

SHIGELLA MEDIATED REGULATION OF EPITHELIAL CELL INFLAMMASOMES - SHIGELLA SPECIES ARE IMPORTANT, HIGHLY INFECTIOUS PATHOGENS OF HUMANS. IN 2016, THERE WERE ~269 MILLION CASES AND 212,000 DEATHS DUE TO SHIGELLA. INFECTION WITH SHIGELLA IS ASSOCIATED WITH INFLAMMATION DUE TO THE RECRUITMENT OF NEUTROPHILS TO THE COLON AND MASSIVE TISSUE DESTRUCTION. DESPITE THIS IMPRESSIVE HOST RESPONSE, SHIGELLA SURVIVE IN THIS HARSH ENVIRONMENT, PRIMARILY BY REPLICATING WITHIN AND SPREADING BETWEEN COLONIC EPITHELIAL CELLS (ECS). SHIGELLA SURVIVE BY DIRECTLY USURPING AND REPROGRAMMING HOST CELL PROCESSES THROUGH THE ACTIVITY OF ~30 TYPE III EFFECTORS, PROTEINS THAT THEY DIRECTLY INJECT INTO THE HOST CELL CYTOSOL VIA A HIGHLY CONSERVED TYPE III SECRETION SYSTEM (T3SS). OUR RESEARCH'S OVERALL GOAL IS TO USE SHIGELLA AS A MODEL PATHOGEN TO DECIPHER THE MECHANISMS THAT ENABLE INTRACELLULAR PATHOGENS TO EVADE HOST INNATE IMMUNE RESPONSES AND ESTABLISH A REPLICATIVE NICHE WITH THE CYTOSOL OF INTESTINAL ECS. WE HAVE A LONG-STANDING INTEREST IN IDENTIFYING AND DECIPHERING ROLES FOR EFFECTORS IN SPECIFIC STEPS IN SHIGELLA PATHOGENESIS. THE FIRST LINE OF DEFENSE THAT SHIGELLA AND OTHER ENTERIC PATHOGENS FACE UPON TRYING TO ESTABLISH A REPLICATIVE NICHE WITHIN THE GASTROINTESTINAL TRACT IS THE INDUCTION OF THE DEATH OF INTESTINAL ECS VIA PYROPTOSIS. PYROPTOSIS IS AN INFLAMMATORY FORM OF CELL DEATH THAT, IF NOT INHIBITED, RESULTS IN THE RAPID LYSIS AND/OR EXPULSION OF INFECTED ECS FROM THE INTESTINAL EPITHELIUM AND THE PROCESSING AND RELEASE OF PRO- INFLAMMATORY CYTOKINES. HERE, WE PROPOSE TO INVESTIGATE HOW SHIGELLA TYPE III SECRETED EFFECTORS COOPERATE TO INHIBIT PYROPTOSIS, THUS ENABLING THIS PROFESSIONAL INTRACYTOPLASMIC PATHOGEN TO ESTABLISH A REPLICATIVE NICHE WITHIN THE CYTOSOL OF INTESTINAL EPITHELIAL CELLS. THESE STUDIES ARE DESIGNED TO SIGNIFICANTLY EXPAND OUR UNDERSTANDING OF HOW SHIGELLA, AND LIKELY OTHER ENTERIC PATHOGENS, INHIBIT INFLAMMASOMES. AT THE COMPLETION OF THE PROPOSED AIMS, IT IS EXPECTED THAT THE KNOWLEDGE GAINED CAN BE APPLIED TOWARDS THE DEVELOPMENT OF NOVEL HOST-BASED INTERVENTIONS FOR THE PREVENTION AND TREATMENT OF ENTERIC INFECTIONS, A PARTICULARLY PRESSING NEED GIVEN EMERGING ISSUES WITH ANTIBIOTIC RESISTANCE.

ECONOMIC ANALYSES OF POLICY STRATEGIES TO IMPROVE DIET AND REDUCE CVD

INTERVENTIONS FOR SUSTAINABLE WEIGHT LOSS IN MILITARY FAMILIES

NRT-HDR DATA DRIVEN DECISION MAKING TO ADDRESS COMPLEX RESOURCE PROBLEMS

READINESS THROUGH INTEGRATIVE SCIENCE AND ENGINEERING: REFINING AND TESTING A CO-CONSTRUCTED CURRICULUM APPROACH WITH HEAD START PARTNERS

MYCOBACTERIUM TUBERCULOSIS ENVIRONMENTAL SIGNAL INTEGRATION: SINGLE CELL IN VIVO UNDERSTANDING OF ITS INFLUENCE ON INFECTION HETEROGENEITY AND TREATMENT EFFICACY

THIS ACTION SETS UP THE NEW AWARD FOR ANTICIPATORY ACTION

ROLE OF HUMAN INNATE IMMUNE MUTATIONS IN LOSS OF TOLERANCE TO BORRELIA BURGDORFERI

HOST CELL REPROGRAMMING BY HUMAN PAPILLOMAVIRUS E7 PROTEINS - PROJECT SUMMARY/ABSTRACT HUMAN PAPILLOMAVIRUS (HPV)-ENCODED PROTEINS ENGAGE CELLULAR PROTEINS TO POTENTLY REPROGRAM HOST CELL SIGNALING PATHWAYS, IN DOING SO ESTABLISHING A CELLULAR ENVIRONMENT CONDUCIVE TO VIRAL REPLICATION AND PERSISTENCE. THE HPV E6 AND E7 PROTEINS PROVIDE MUCH OF THE VIRAL REPROGRAMMING ACTIVITY AND, IN THE CASE OF ‘HIGH-RISK’ HPV E6 AND E7, SO SIGNIFICANTLY DISRUPT CELL SIGNALING THAT THEY PROMOTE CELLULAR TRANSFORMATION. INTENSIVE RESEARCH EFFORTS HAVE IDENTIFIED MANY HOST CELL BINDING PARTNERS OF HPV E7, SOME THAT INTERACT WITH HPV E7 PROTEINS FROM MOST VIRUS GENOTYPES AND OTHERS THAT INTERACT WITH ONLY A SUBSET OF THE HPV E7S. HOWEVER, THERE IS A MAJOR OPEN QUESTION REGARDING HOW MANY OF THE HOST CELL TARGETS OF HIGH-RISK AND LOW-RISK HPV E7 PROTEINS ARE REQUIRED TO REPROGRAM HOST CELL SIGNALING AND, FOR HIGH-RISK HPV E7, TO DRIVE CELLULAR TRANSFORMATION. WE PROPOSE THAT THE RB1 AND PTPN14 TUMOR SUPPRESSORS ARE TWO ESSENTIAL E7 TARGETS AND THEIR INACTIVATION DOMINATES THE BIOLOGICAL ACTIVITY OF E7. RB1 IS A WELL-KNOWN TARGET OF MANY HPV E7 PROTEINS THAT MUST BE INACTIVATED FOR HIGH-RISK HPV TO CAUSE CELLULAR TRANSFORMATION. HIGH-RISK HPV E7 PROTEINS CAN DEGRADE RB1, WHICH IS NOT A PROPERTY OF LOW-RISK HPV E7S. IT IS NOT KNOWN HOW RB1 DEGRADATION, IN ADDITION TO BINDING, ENABLES HIGH-RISK HPV E7 TO ALTER CELL SIGNALING OR TO PROMOTE CELLULAR TRANSFORMATION. MOREOVER, RB1 INACTIVATION IS NECESSARY BUT INSUFFICIENT FOR THE TRANSFORMING ACTIVITY OF HIGH-RISK HPV E7. WE DISCOVERED THAT A SECOND TARGET OF MANY HPV E7 PROTEINS IS PTPN14. OUR PUBLISHED AND PRELIMINARY DATA SHOW THAT HPV E7 PROTEINS DEGRADE PTPN14 AND THAT PTPN14 DEGRADATION ACTIVATES YAP1 SIGNALING. WE ALSO FOUND THAT HIGH-RISK HPV E7 MUST DEGRADE PTPN14 AND ACTIVATE YAP1 TO IMMORTALIZE PRIMARY HUMAN KERATINOCYTES. OUR HYPOTHESIS IS THAT RB1 DEGRADATION AND PTPN14 DEGRADATION ARE INDEPENDENT ACTIVITIES OF HIGH-RISK HPV E7 PROTEINS THAT COOPERATE TO REPROGRAM THE HOST CELL AND DRIVE CELL TRANSFORMATION. THE AIMS ARE 1) TO DETERMINE HOW DEGRADATION OF RB1 AND PTPN14 CONTRIBUTE TO HOST CELL REPROGRAMMING AND 2) TO DETERMINE HOW DEGRADATION OF PTPN14 AND RB1 CONTRIBUTE TO HPV E7 TRANSFORMING ACTIVITY. OUR RESEARCH WILL DETERMINE HOW HPV E7 REPROGRAMS HOST CELL SIGNALING AND HOW INHIBITING ESSENTIAL ACTIVITIES OF HPV E7 COULD LIMIT CELL GROWTH. BY TESTING WHETHER A SUBSET OF THE MANY PROPOSED TARGETS OF HPV E7 UNDERLIE MOST OF ITS BIOLOGICAL ACTIVITY, WE WILL ADVANCE THE UNDERSTANDING OF VIRAL ONCOPROTEIN ACTIVITY, UPDATING THE MODEL TO REFLECT THE ESTABLISHED CONCEPT THAT ALTERING A SMALL NUMBER OF HOST TARGETS IS SUFFICIENT FOR CELLULAR TRANSFORMATION.

CORNEAL-EPITHELIAL NUCLEAR FERRITIN AND U.V. PROTECTION

DEFINING THE ROLE OF ALTERNATIVE POLYADENYLATION IN MACROPHAGE DIFFERENTIATION AND FUNCTION

TUFTS UNIVERSITY: NEW AWARD WITH CONTROL#3117-1509 UNDER DE-FOA-0003117 - REVOLUTIONIZING ORE TO STEEL TO IMPACT EMISSIONS (ROSIE) TITLED ''SOLVING ORE CONCENTRATE REDUCTION WITH NEW CHEMISTRY'' TUFTS WILL REVITALIZE THE U.S. ORE-TO-IRON VALUE CHAIN BY DIRECTLY REDUCING IRON ORE CONCENTRATES WITH AMMONIA—ELIMINATING CO2 EMISSIONS WHILE DECREASING COSTS. TUFTS APPROACH WILL ELIMINATE ALL DIRECT PROCESS EMISSIONS FROM THE IRONMAKING STEP (1.4 T CO2/T HOT ROLLED COIL STEEL FOR BLAST FURNACE IRONMAKING) AND 0.25 T CO2/T HRC FROM INDURATION OF IRON ORE PELLETS. OUR METHOD SAVES 10-25% OF THE TOTAL COST OF HRC, OR MORE IF USING LOWER-GRADE ORES. THESE BENEFITS RESULT FROM THE NEW CHEMISTRY AND NEW LEARNING CURVES AFFORDED BY NH3.

UNDERSTANDING AND DESIGNING CYCLIC PEPTIDES

ROLE OF LISTERIA CODY IN INTEGRATING METABOLISM AND VIRULENCE

SINGLE-CELL FACTORS OF TUBERCULOSIS DRUG TOLERANCE DURING ADAPTATION TO ENVIRONMENTAL STRESSORS

REGULATION OF ASTROCYTE HETEROGENEITY AND DEVELOPMENTAL MATURATION IN THE CNS

MATERNALLY TRANSMITTED OPIATE ABUSE VULNERABILITY

REGIONAL ENHANCED LIVELIHOODS FOR PASTORAL AREAS (RELPA) PROGRAM PASTORAL AREAS COORDINATION, ANALYSIS, AND POLICY SUPPORT ACTIVITY (PACAPS).

NEURONAL/GLIAL EXOSOME SIGNALING AND BETA-AMYLOID PROPAGATION IN ALZHEIMER'S DISEASE (AD)

NUTRITION RESEARCH FOR HEALTH AGING AND PREVENTION OF CHRONIC DISEASE

VITAMIN K AND D AND COGNITIVE IMPAIRMENT IN OLDER ADULTS - PROJECT SUMMARY IDENTIFICATION OF DIETARY FACTORS THAT DELAY DECLINE IN COGNITIVE FUNCTION HAS IMPORTANT IMPLICATIONS FOR REDUCING THE BURDEN OF ALZHEIMER’S DEMENTIA (AD) AND REDUCING HEALTH CARE COSTS AS THE POPULATION AGES. INADEQUATE INTAKES OF VITAMIN K AND VITAMIN D ARE COMMON AMONG THE ELDERLY, AND THERE IS GROWING EVIDENCE THAT BOTH NUTRIENTS HAVE BIOLOGICAL ROLES IN THE PATHOGENESIS OF ALZHEIMER’S DISEASE (AD) AND RELATED PATHOLOGIES, AND THE RISK OF ALZHEIMER’S DEMENTIA. WE DEMONSTRATED IN THE RUSH MEMORY AND AGING PROJECT (MAP) STUDY THAT HIGHER POSTMORTEM BRAIN LEVELS OF VITAMIN K AND VITAMIN D WERE ASSOCIATED WITH BETTER COGNITIVE FUNCTION PRIOR TO DEATH. FURTHER INVESTIGATION OF NEUROPATHOLOGICALLY-DEFINED OUTCOMES REVEALED THAT HIGHER BRAIN VITAMIN K CONCENTRATIONS WERE ASSOCIATED WITH LOWER GLOBAL AD PATHOLOGY, SPECIFICALLY FEWER NEUROFIBRILLARY TANGLES, AND WITH LESSER LEWY BODIES (SINE QUA NON OF PARKINSON’S DISEASE AND LEWY BODY DEMENTIA). THERE IS NOW AN URGENT NEED FOR ADDITIONAL RESEARCH TO CLARIFY THE BIOLOGIC MECHANISM(S) UNDERLYING THESE COGNITIVE PROTECTIVE EFFECTS. BASED ON OUR COLLECTIVE PRIOR RESEARCH AND EXCITING NEW RESEARCH FINDINGS GENERATED DURING THE CURRENT PROJECT PERIOD, WE PROPOSE AN OVERALL GOAL TO ELUCIDATE ASSOCIATIONS BETWEEN VITAMIN K AND VITAMIN D WITH BRAIN STRUCTURE (NEUROPATHOLOGY AND NEUROIMAGING OUTCOMES) AND BRAIN FUNCTION (COGNITIVE AND MOTOR) IN OLDER PERSONS FROM TWO WELL-CHARACTERIZED COMMUNITY-BASED STUDIES, MAP AND THE RUSH MINORITY AGING RESEARCH STUDY (MARS). GUIDED BY STRONG PRELIMINARY DATA, THIS OBJECTIVE WILL BE ACCOMPLISHED BY PURSUING TWO AIMS: SPECIFIC AIM 1: DETERMINE ASSOCIATIONS OF VITAMIN K AND VITAMIN D WITH MRI-DERIVED INDICES OF WHITE AND GRAY MATTER TISSUE INTEGRITY AND MEASURES OF BRAIN NEUROPATHOLOGY IN: (A) POSTMORTEM BRAIN SAMPLES; AND (B) ANTEMORTEM BLOOD SAMPLES; AND SPECIFIC AIM 2: DETERMINE THE ASSOCIATIONS OF BRAIN VITAMIN K AND VITAMIN D WITH MOTOR FUNCTION AND PARKINSONIAN SIGNS. THE PROPOSED APPROACH IS INNOVATIVE BECAUSE THIS HIGHLY PRODUCTIVE AND MULTIDISCIPLINARY TEAM WILL: (1) EXPAND OUR BRAIN STRUCTURE OUTCOMES TO INCLUDE NEUROIMAGING THAT LEVERAGE NOVEL DEEP-LEARNING APPROACHES, IN ADDITION TO NEUROPATHOLOGIC OUTCOMES, TO DETERMINE IF THESE TWO VITAMINS ARE INVOLVED IN CHANGES IN BRAIN TISSUE INTEGRITY THAT OCCUR IN AD AND RELATED PATHOLOGIES; (2) EXPAND BRAIN FUNCTION OUTCOMES TO INCLUDE EXISTING OUTCOMES OF MOTOR FUNCTION AND PARKINSONIAN SIGNS, IN ADDITION TO COGNITIVE OUTCOMES, FOR NOVEL INSIGHT INTO COMMON MECHANISMS UNDERLYING AGE-RELATED COGNITIVE AND PHYSICAL FUNCTION DECLINES; AND (3) ADD AFRICAN-AMERICAN DECEDENTS WITH AUTOPSIES FROM MARS TO ENHANCE GENERALIZABILITY OF THE FINDINGS. THE PROPOSED RESEARCH IS SIGNIFICANT BECAUSE INTAKES OF THESE TWO NUTRIENTS, WHICH ARE GENERALLY BELOW THE RECOMMENDED AMOUNTS IN OLDER PERSONS, ARE MODIFIABLE, LOW-COST, AND SAFE WHEN CONSUMED IN HIGHER AMOUNTS. SUCCESSFUL COMPLETION OF THE PROPOSED STUDY WILL PROVIDE THE FOUNDATION FOR FUTURE STUDIES ON THE IMPACT OF MODIFYING VITAMIN K AND/OR VITAMIN D ON AD RISK.

VISTA STATE

IGERT: SOFT MATERIAL ROBOTICS

IN VITRO BIOREACTOR SYS FOR PLATELET FORMATION

NANOSTRUCTURED, METAL ION MODIFIED CERIA AND ZIERCONIA OXIDATION CATALYSTS

GLOBAL TRANSCRIPTOME ANALYSIS OF MUCOSAL GONOCCAL INFECTION

ROLE OF BACE STABILIZATION IN AD

CONTROL OF ENDOPLASMIC RETICULUM TUBULE FORMATION BY LEGIONELLA PNEUMOPHILA

TISSUE ENGINEERING CORNEA REPLACEMENTS

GENERATION OF TUMOR SPECIFIC IMMUNITY IN CANINE OSTEOSARCOMA THROUGH DENDRITIC CELL HYPERACTIVATION - PROJECT SUMMARY DESPITE SUBSTANTIAL IMPROVEMENTS IN THERAPEUTIC STRATEGIES, GENERATING ROBUST ANTI-TUMOR IMMUNE RESPONSES IN HUMAN CANCERS WITH A LOWER SOMATIC MUTATION BURDEN REMAINS A SUBSTANTIAL CHALLENGE. RECENT DATA INDICATE THAT A CRITICAL PLAYER IN THIS PROCESS, DENDRITIC CELLS (DCS), FAIL TO EFFECTIVELY ELICIT EFFICIENT AND DURABLE T CELL RESPONSES UNLESS THEY HAVE ENTERED A UNIQUE STATE OF HYPERACTIVATION. IN THIS SETTING, DCS EXHIBIT ENHANCED MIGRATION TO LOCAL LYMPH NODES (LNS) AND SUSTAINED SECRETION OF IL-1SS, A CYTOKINE CRITICAL FOR MEMORY T CELL FORMATION. IN MOUSE TUMOR MODELS, VACCINATION WITH WHOLE TUMOR LYSATE PLUS AN ADJUVANT CONSISTING OF THE TLR 7/8 AGONIST R848 (RESIQUIMOD) IN COMBINATION WITH A UNIQUE ISOLATED LYSOPHOSPHATIDYLCHOLINE (22:0 LYSO PC) PROMOTES DC HYPERACTIVATION, EXPANSION OF ANTIGEN SPECIFIC CD8+ T CELLS, AND ROBUST REJECTION OF TUMORS. WHILE THESE FINDINGS ARE ENCOURAGING AND SUGGEST THAT IDENTIFICATION OF SPECIFIC NEOANTIGENS IS NOT NECESSARY TO PRIME AND EXPAND A POOL OF CYTOTOXIC T CELLS (CTLS), VALIDATION AND OPTIMIZATION OF THIS APPROACH NECESSITATES THE USE OF A MODEL SYSTEM THAT MORE CLOSELY RECAPITULATES HUMAN CANCERS WITH RESPECT TO IMMUNE LANDSCAPE. AS SUCH, THE PURPOSE OF THIS PROPOSAL IS TO USE SPONTANEOUS CANINE CANCER, SPECIFICALLY OSTEOSARCOMA (OS), AS A BRIDGING ANIMAL MODEL TO VALIDATE THE UTILITY OF DC HYPERACTIVATION AS A FOUNDATIONAL ELEMENT FOR GENERATION OF ROBUST ANTI-TUMOR IMMUNITY. THE CENTRAL HYPOTHESIS TO BE TESTED IN THIS APPLICATION IS THAT COMBINING HYPERACTIVATION OF DCS WITH WTL DERIVED NEOANTIGEN WILL EXPAND A DIVERSE AND TUMOR-SPECIFIC POPULATION OF CTLS CAPABLE OF ELIMINATING RESIDUAL MICROSCOPIC METASTATIC OS TUMOR CELLS IN DOGS FOLLOWING PRIMARY TUMOR REMOVAL (AMPUTATION). WE FURTHER PREDICT, THAT COMBINING DC HYPERACTIVATION/WTL WITH A NOVEL TUMOR MICROENVIRONMENT (TME) CONDITIONING REGIMEN CONSISTING OF TOCERANIB/LOSARTAN/LADARIXIN WILL ENHANCE THE OBJECTIVE RESPONSE RATE IN DOGS THAT DEVELOP MACROSCOPIC LUNG METASTASIS. TO ACCOMPLISH THIS, WE WILL CONDUCT A PROSPECTIVE RANDOMIZED CLINICAL TRIAL IN DOGS WITH OS COMBINING AMPUTATION AND STANDARD OF CARE CARBOPLATIN CHEMOTHERAPY WITH ADJUVANT ALONE OR ADJUVANT+WTL. DOGS THAT DEVELOP LUNG METASTASIS WILL THEN BE TREATED WITH THE TME CONDITIONING REGIMEN IN COMBINATION WITH ADJUVANT+WTL. A BIOBANK OF TISSUE SAMPLES AND BLOOD WILL BE COLLECTED FROM DOGS ENROLLED IN THESE TRIALS INCLUDING MATCHED PRIMARY/METASTATIC TUMORS AND ASSOCIATED LNS, WHOLE BLOOD, PLASMA, PBMCS, CELL-FREE DNA, AND SAMPLES FROM THE VACCINE DRAINING LNS. THESE WILL BE USED TO PERFORM A SET OF COMPLEMENTARY ASSAYS DESIGNED TO CHARACTERIZE THE IMMUNE MICROENVIRONMENT AND TUMOR GENOME OVER THE COURSE OF RELAPSE/RESISTANCE, CREDENTIAL A NOVEL NEOANTIGEN PREDICTION PIPELINE, AND EVALUATE ANTIGEN SPECIFIC T CELL RESPONSES. AN OUTSTANDING TEAM WITH COMPLEMENTARY SETS OF EXPERTISE ACROSS CLINICAL TRIALS, TRANSLATIONAL ONCOLOGY, COMPARATIVE GENOMICS, AND IMMUNO-ONCOLOGY HAS BEEN ASSEMBLED TO ENSURE STATED MILESTONES ARE ACHIEVED. THIS IS BOLSTERED BY A DYNAMIC COLLABORATION WITH OUR INDUSTRY PARTNER, CORNER THERAPEUTICS, WHICH IS COMMITTED TO SUPPORTING THIS WORK TO FACILITATE OPTIMIZATION AND SUCCESSFUL TRANSLATION INTO HUMAN PATIENTS.

POST-TRANSCRIPTIONAL REGULATION OF GENE EXPRESSION BY MICRORNAS IN ANTIBODY-MEDIATED REJECTION - CHRONIC ANTIBODY-MEDIATED REJECTION (AMR) IS A MAJOR CAUSE OF RENAL ALLOGRAFT REJECTION. YET DESPITE ITS CLINICAL IMPORTANCE AN INTEGRATED UNDERSTANDING OF HOW RESPONSES TO ANTIBODY AND COMPLEMENT MEDIATED ATTACK ARE REGULATED BY THE TRANSPLANTED KIDNEY HAS NOT BEEN ESTABLISHED. THIS GAP IN OUR KNOWLEDGE IS DUE AT LEAST IN PART TO AN INCOMPLETE UNDERSTANDING OF RESPONSES MADE BY THE KIDNEY THAT RESULT IN GENE REGULATION PROMOTE OR PREVENT INJURY. MICRORNAS (MIRNAS) ARE A CLASS OF SMALL NONCODING RNAS THAT REGULATE GENE EXPRESSION POST-TRANSCRIPTIONALLY. MIRNAS PLAY AN IMPORTANT ROLE IN REGULATING RENAL INJURY. HOWEVER, THE STUDY OF MIRNAS IN REJECTION AND RENAL INJURY HAS LARGELY BEEN BASED ON ANALYSIS OF TOTAL CELLULAR MIRNAS THAT ARE DIFFERENTIALLY EXPRESSED DURING DISEASE. THIS APPROACH IS PROBLEMATIC BECAUSE IT DOES NOT PROVIDE INFORMATION ON THE MRNAS TARGETED BY THESE MIRNAS. TO ADDRESS THIS ISSUE, WE ASKED WHETHER IT IS POSSIBLE TO ISOLATE MIRNAS AND THE MRNAS THEY ARE TARGETING IN THE RNA-INDUCED SILENCING COMPLEX (RISC) BY ISOLATING RNAS CROSS-LINKED TO THE RNA BINDING PROTEIN (RBP) AGO2. USING THIS APPROACH WE DEFINED THE FIRST MIRNA-MRNA INTERACTION MAP FOR TRANSPLANT RELATED RENAL INJURY. THESE PROOF-OF-PRINCIPLE STUDIES REVEALED THAT WITHIN THE MIRNA-MRNA TARGETOME IT IS POSSIBLE TO DEFINED MIRNAS AND THE MRNAS THEY TARGET THAT UNDERGO UNIQUE CHANGES IN CELLS UNDERGOING INJURY. PATHWAY ENRICHMENT ANALYSIS INDICATED THAT MIRNAS PRESENT IN THE RISC COMPLEX TARGET MRNAS ENCODING PROTEINS IN PATHWAYS THAT MAY CONTRIBUTE TO INJURY. BASED ON THESE STUDIES, WE HYPOTHESIZE THAT THE MIRNA-MRNA TARGETOME CAN BE USED TO IDENTIFY GENE PATHWAYS THAT CONTRIBUTE TO AMR. TO TEST THIS HYPOTHESIS, WE WILL USE A CLINICALLY RELEVANT MURINE MODEL TO DETERMINE THE MIRNA-MRNA MAP FOR AMR AND USE INFORMATION ELUCIDATED BY THE TARGETOME TO EXAMINE GENE PATHWAYS UNDER REGULATION BY MIRNAS. WE EXAMINE THE CLINICAL RELEVANCE OF OUR FINDINGS BY EXAMINING WHETHER SIMILAR CHANGES OCCUR IN HUMAN KIDNEY TRANSPLANTS. THESE STUDIES WILL PROVIDE UNIQUE INSIGHT INTO PROCESS THAT DRIVE PATHOLOGY ASSOCIATED WITH AMR, INFORMATION THAT COULD BE USED TO DISTINGUISH AMR FROM OTHER TYPES OF INJURY, AND PROVIDES A NOVEL RESOURCE TO THE TRANSPLANTATION AND WIDER SCIENTIFIC COMMUNITY.

SILICA-PROTEIN NANOCOMPOSITES FOR DENTAL REPAIR

ROLE OF LACRIMAL GLAND MYOEPITHELIAL CELLS IN DRY EYE DISEASE

STUCTURAL STUDIES OF TRIPLE-HELICAL PROTEINS

EMERGENCE OF TICK BORNE ENCEPHALITIS IN NORTH AMERICA

INCREMENTAL FUNDING - RE-EXAMINING EARLY WARNING SYSTEMS AND HUMANITARIAN RESPONSES IN PASTORAL AREAS OF THE SUDANO-SAHEL AND THE GREATER HORN OF AFRICA

GENETIC ANALYSIS OF RAS AND G PROTEIN FUNCTION

IPSC-DERIVED REPAIR-RESPONSIVE FIBROBLASTS TO HEAL DIABETIC FOOT ULCERS

ASSESSING AND PREVENTING OBESITY AMONG NEW IMMIGRANTS

COHERENT HEMODYNAMICS SPECTROSCOPY FOR CEREBRAL AUTOREGULATION AND BLOOD FLOW

MECHANISMS OF BREAST CANCER ASSOCIATED WITH OBESITY

DEVELOPING AUTOPHAGY-TARGETING CHIMERAS AND OPTIMIZING CELL PENETRATION OF LARGE-MOLECULE THERAPEUTICS - THE KRITZER LAB FOCUSES ON INHIBITING PROTEIN-PROTEIN INTERACTIONS INVOLVED IN AUTOPHAGY. AUTOPHAGY IS A PROTEIN DEGRADATION PATHWAY THAT IS ACTIVE IN ALL HUMAN CELLS, AND INHIBITING AUTOPHAGY SHOWS PROMISE AS A THERAPY FOR LATE-STAGE CANCERS ESPECIALLY IN COMBINATION WITH DNA-DAMAGING CHEMOTHERAPIES. AUTOPHAGY RESEARCH AND DRUG DEVELOPMENT CURRENTLY RELY ON COMPOUNDS THAT INHIBIT AUTOPHAGY INDIRECTLY. BETTER, MORE SPECIFIC INHIBITORS OF AUTOPHAGY WOULD BE BROADLY ADOPTED. A LARGE AMOUNT OF GENETICS AND CELL BIOLOGY WORK SUPPORTS THAT INHIBITING THE LC3/GABARAP FAMILY OF PROTEINS CAN BLOCK AUTOPHAGY SELECTIVELY. IN ONE SERIES OF PROJECTS, WE WILL DEVELOP NOVEL STAPLED PEPTIDE AND SMALL MOLECULE INHIBITORS OF LC3/GABARAP AND EVALUATE THEM IN MODELS OF LATE-STAGE CANCERS AND OTHER DISEASES. BECAUSE OF OUR EXPERTISE IN COMPOUNDS THAT BIND LC3/GABARAP PROTEINS, WE ALSO PROPOSE TO EVALUATE RELATED COMPOUNDS AS AUTOPHAGY-TARGETING CHIMERAS (AUTACS). THESE COMPOUNDS COULD BE USED TO SELECTIVELY DEGRADE ANY PROTEINS IN THE CELL, SIMILAR TO PROTEOLYSIS-TARGETING CHIMERAS (PROTACS) BUT POTENTIALLY MORE VERSATILE AND EASIER TO DEVELOP. BASED ON STRONG PRELIMINARY DATA THAT VALIDATE THE AUTAC CONCEPT, WE WILL DEVELOP NOVEL AUTACS AND DEMONSTRATE THEIR ABILITY TO DEGRADE ENDOGENOUS PROTEINS, UNLOCKING A BROAD NEW AREA FOR DRUG DEVELOPMENT IN TARGETED PROTEIN DEGRADATION. OVER THE COURSE OF DEVELOPING STAPLED PEPTIDES AS AUTOPHAGY MODULATORS, THE KRITZER LAB ENCOUNTERED A COMMON PROBLEM IN THE FIELD: HOW TO MEASURE THE AMOUNT THAT ACTUALLY REACHES THE CYTOSOL. IN AN INDEPENDENT SERIES OF PROJECTS, THE KRITZER LAB HAS DEVELOPED NOVEL ASSAYS THAT QUANTITATE THE CYTOSOLIC PENETRATION OF LARGE-MOLECULE THERAPEUTICS. IN THIS PROPOSAL, WE DESCRIBE NEW OPPORTUNITIES TO ADDRESS CHALLENGING PROBLEMS IN DRUG DEVELOPMENT FOR LARGE-MOLECULE THERAPEUTICS. WE DESCRIBE NEW METHODS TO MEASURE PENETRATION TO DIFFERENT CELLULAR COMPARTMENTS IN ANY CELL TYPE, INCLUDING PRIMARY CELLS. WE ALSO DESCRIBE A MOLECULAR EVOLUTION APPROACH TO DEVELOP A NEW “TURN-ON” ASSAY THAT MEASURES THE REAL-TIME KINETICS OF CYTOSOLIC PENETRATION. WE DESCRIBE POOLED CRISPR SCREENS TO REVEAL THE CELLULAR COMPONENTS THAT MEDIATE ENDOSOMAL ESCAPE. FINALLY, WE DESCRIBE A NOVEL SCREENING PLATFORM THAT WILL ALLOW US TO SCREEN THOUSANDS TO MILLIONS OF MOLECULES AT A TIME FOR THOSE THAT ARE MOST CELL-PENETRANT; THE NEW SCREEN WILL BE INCORPORATED INTO A DESIGN-TEST-LEARN CYCLE TO PRODUCE DATA-DRIVEN DESIGN ALGORITHMS FOR CYTOSOL-PENETRANT MOLECULES. ALL TOGETHER, THESE DATA WILL REPRESENT A HUGE LEAP IN OUR UNDERSTANDING OF STRUCTURE-PENETRATION RELATIONSHIPS FOR SEVERAL CLASSES OF LARGE-MOLECULE THERAPEUTICS.

THE ROLE OF BETA-CATENIN IN THE PATHOPHYSIOLOGY OF INFANTILE SPASMS

C ALBICANS IN THE GI TRACT ENVIRONMENT

COMMUNITY ASSESSMENT OF FREEWAY POLLUTION AND HEALTH

STRESS-INDUCED IMPAIRMENTS IN ENDOGENOUS NEUROSTEROID SIGNALING IN THE BLA NEGATIVELY IMPACTS NETWORK AND BEHAVIORAL STATES - PROJECT SUMMARY THE EPISODIC NATURE OF PSYCHIATRIC DISORDERS SUGGESTS THAT THE BRAIN SHIFTS BETWEEN PATHOLOGICAL AND HEALTHY BRAIN STATES. FEAR AND ANXIETY HAVE BEEN CORRELATED WITH CHANGES IN OSCILLATIONS BETWEEN THE MEDIAL PREFRONTAL CORTEX (MPFC) AND BASOLATERAL AMYGDALA (BLA) AND ABNORMALITIES IN THESE NETWORKS HAVE BEEN IDENTIFIED IN PATIENTS WITH A RANGE OF PSYCHIATRIC DISORDERS AND WE PROPOSE THAT THESE NETWORKS MAY IMPACT EMOTIONAL PROCESSING MORE BROADLY. HOWEVER, WE UNDERSTAND VERY LITTLE ABOUT THE MECHANISM(S) WHEREBY NETWORKS SHIFT BETWEEN STATES. 5A-REDUCED NEUROSTEROIDS, INCLUDING ALLOPREGNANOLONE, HAVE BEEN SUGGESTED TO PLAY A ROLE IN AFFECTIVE SWITCHING AND HAVE BEEN SHOWN TO EXERT ROBUST ANXIOLYTIC AND ANTIDEPRESSANT EFFECTS IN PRECLINICAL MODELS AND IN CLINICAL TRIALS. IN FACT, AN ALLOPREGNANOLONE ANALOG RECENTLY RECEIVED FDA APPROVAL FOR THE TREATMENT OF POSTPARTUM DEPRESSION. THE CURRENT STUDY BUILDS ON THESE FINDINGS TO INVESTIGATE THE POTENTIAL ROLE OF ENDOGENOUS NEUROSTEROIDS IN MEDIATING TRANSITIONS BETWEEN HEALTHY AND UNHEALTHY NETWORK AND BEHAVIORAL STATES. GIVEN THAT STRESS HAS BEEN IMPLICATED IN NUMEROUS PSYCHIATRIC DISORDERS, WE PROPOSE TO UTILIZE A CHRONIC UNPREDICTABLE STRESS (CUS) MODEL TO EVALUATE THE IMPACT ON MPFC-BLA NETWORK FUNCTION. WE PROPOSE THAT STRESS DISRUPTS NETWORK FUNCTION BY IMPAIRING LOCAL NEUROSTEROID SIGNALING IN THE BLA (SUPPORTED BY PRELIMINARY DATA) AND THAT INCREASING THE CAPACITY FOR ENDOGENOUS NEUROSTEROIDOGENESIS CAN RESTORE HEALTHY NETWORK FUNCTION. OUR PROPOSED MECHANISM INVOLVES THE ACTION OF NEUROSTEROIDS ON GABAAR D SUBUNIT-CONTAINING RECEPTORS, EXPRESSED AT A HIGH DENSITY IN PARVALBUMIN (PV)-POSITIVE NEURONS IN THE BLA, WHICH ARE KNOWN TO MODULATE OSCILLATIONS WITHIN AND BETWEEN THE MPFC-BLA. THUS, THIS APPLICATION WILL TEST THE HYPOTHESIS THAT DEFICITS IN ENDOGENOUS 5A-REDUCED NEUROSTEROID SIGNALING IN THE BLA, VIA D-SUBUNIT CONTAINING GABAARS ON PV INTERNEURONS, CONTRIBUTE TO THE STRESS-INDUCED IMPAIRMENTS IN NETWORK AND BEHAVIORAL STATES.

OXYCODONE, NEONATAL OPIOID WITHDRAWAL SYNDROME, AND ADULT ABUSE LIABILITY

REGULATION OF T CELL IMMUNE RESPONSE IN HEART FAILURE WITH PRESERVED EJECTION FRACTION - THE GOAL OF THIS R01 APPLICATION IS TO INVESTIGATE THE MECHANISMS BY WHICH T CELLS CONTRIBUTE TO HEART FAILURE (HF) WITH PRESERVED EJECTION FRACTION (HFPEF), AFFECTING ROUGHLY 50% OF THE HF PATIENTS. NOTABLY, THE TREATMENTS THAT IMPROVE SURVIVAL AND OUTCOMES IN PATIENTS WITH HF WITH REDUCED EJECTION FRACTION (HFREF) HAVE NOT PROVIDED CLINICAL BENEFIT IN HFPEF PATIENTS, WHO OFTEN PRESENT WITH MULTIPLE COMORBIDITIES THAT INCLUDE OBESITY AND HYPERTENSION. CORRELATIVE EPIDEMIOLOGICAL STUDIES IN HFPEF PATIENTS, SUGGEST A POTENTIAL CONTRIBUTION OF INFLAMMATION TO HFPEF. HOWEVER THE UNDERLYING IMMUNE MECHANISMS REMAIN LARGELY UNEXPLORED. A UNIQUE MYOCARDIAL HALLMARK OF HUMAN HFPEF REPLICATED IN A PRE-CLINICAL MODEL OF CARDIOMETABOLIC HFPEF IS THE DOWNREGULATION OF THE UNFOLDED PROTEIN RESPONSE (UPR), WHICH RESULTS IN THE CELLULAR INABILITY TO COPE WITH ENDOPLASMIC RETICULUM (ER) STRESS, THE CENTRAL FUNCTION OF THE UPR, THUS IMPAIRING CARDIOMYOCYTE RELAXATION. OUR PRELIMINARY DATA USING AN EXPERIMENTAL MODEL OF CARDIOMETABOLIC HFPEF REVEAL THE NOVEL FINDING THAT CARDIAC T CELL INFILTRATION CO-EXISTS WITH DIASTOLIC DYSFUNCTION AND CARDIOMYOCYTE HYPERTROPHY, AND THAT T CELL DEFICIENT MICE (TCRA-/-) DO NOT DEVELOP DIASTOLIC DYSFUNCTION OR CARDIOMYOCYTE HYPERTROPHY UNDER THE SAME CONDITIONS. OUR DATA ALSO REVEAL THAT GENES ENCODING SPECIFIC ER STRESS RESPONSE FACTORS SUCH AS X-BOX PROTEIN 1 (XBP1S) AND ACTIVATING TRANSCRIPTION FACTOR 6 (ATF6), ARE REMARKABLY DOWNREGULATED IN CD4+ T CELLS ISOLATED FROM MICE WITH CARDIOMETABOLIC HFPEF, AND NOT IN T CELLS FROM MICE WITH HFREF. T CELL DOWNREGULATION OF XBP1S HAS BEEN IMPLICATED IN ENHANCED T CELL EFFECTOR FUNCTION AND ANTI-TUMOR ACTIVITY. THIS PROPOSAL WILL TEST THE CENTRAL HYPOTHESIS THAT DYSREGULATION OF T CELL- INTRINSIC ER STRESS RESPONSES PROMOTES DETRIMENTAL INFLAMMATION IN CARDIOMETABOLIC HFPEF. IN AIM1, WE WILL USE SINGLE CELL ANTIBODY AND RNA SEQUENCING (CITE-SEQ) TO UNCOVER THE T CELL TRANSCRIPTIONAL PROFILES THROUGHOUT THE DEVELOPMENT OF CARDIOMETABOLIC HFPEF IN WT MICE, INVESTIGATE THE ANTIGEN DEPENDENCE OF THE T CELL RESPONSE, THE DOMINANT T CELL SUBSETS INVOLVED, AND THEIR ABILITY TO RESCUE THE PROTECTIVE PHENOTYPE OBSERVED IN TCRA-/- RECIPIENT MICE. IN AIM 2, WE WILL DETERMINE THE EXPRESSION OF THE T CELL UPR DURING THE PROGRESSION OF CARDIOMETABOLIC HFPEF AND UTILIZE GAIN-AND LOSS-OF- FUNCTION APPROACHES TO DEFINE THE MECHANISMS BY WHICH THE T CELL UPR IS COMPROMISED IN CARDIOMETABOLIC HFPEF AND IMPACTS T CELL PRO- INFLAMMATORY EFFECTOR FUNCTION. IN AIM 3, WE WILL INVESTIGATE THE FUNCTIONAL ROLE OF THE T CELL-INTRINSIC ER STRESS RESPONSE IN CARDIOMYOCYTE HYPERTROPHY AND FUNCTION DURING THE PROGRESSION OF HFPEF AND THE T CELL DERIVED FACTORS ALTERED BY THE COMPROMISED UPR THAT IMPACT CARDIOMYOCYTE HYPERTROPHY AND FUNCTION, USING MICE SELECTIVELY LACKING UPR EFFECTORS IN T CELLS, AND GAIN OF FUNCTION APPROACHES,. SUCCESSFUL ACCOMPLISHMENT OF THE AIMS PROPOSED IS EXPECTED TO IDENTIFY NOVEL T CELL INTRINSIC MECHANISMS THAT FOSTER DETRIMENTAL IMMUNE RESPONSES IN HFPEF, PAVING THE WAY FOR THE DEVELOPMENT OF NEW IMMUNOMODULATORY STRATEGIES TO CONFRONT THIS DEADLY SYNDROME.

TUFTS CTSI CAREER DEVELOPMENT PROGRAM IN COMPARATIVE EFFECTIVENESS RESEARCH

IMMUNOMODULATORY MECHANISMS OF WILD BIRD RESERVOIR HOSTS THAT FACILITATE PERSISTENCE OF LYME DISEASE BACTERIA - PROJECT SUMMARY. LYME DISEASE (LD) IS THE MOST COMMON VECTOR-BORNE ILLNESS IN THE NORTHERN HEMISPHERE, WITH AN ESTIMATED 476,000 NEW CASES ANNUALLY IN THE US. NO EFFECTIVE PREVENTION IS CURRENTLY AVAILABLE. THE DISEASE IS CAUSED BY INFECTION WITH BORRELIA BURGDORFERI (BB) WHICH IS TRANSMISSION BY IXODES TICKS. AFTER INOCULATION IN THE SKIN, BB DISSEMINATES TO DIFFERENT ORGANS, PRESUMABLY BY EVADING HOST IMMUNE RESPONSES, INCLUDING COMPLEMENT- AND ANTIBODY-MEDIATED KILLING. WHILE BB DOES NOT CAUSE SYMPTOMS IN RESERVOIR HOSTS, SUCH AS PEROMYSCUS MICE (WHITE FOOTED MICE) AND WILD BIRDS, IT PERSISTS IN THESE ANIMALS AND CAN THUS BE TRANSMITTED TO HUMANS BY TICK BITE. OUR OVERREACHING GOAL IS TO IDENTIFY THE MECHANISMS THAT FACILITATE PERSISTENCE OF BB IN NATURAL RESERVOIR HOSTS, WHICH CAN ULTIMATELY FACILITATE THE UNDERSTANDING OF BIRD-SPECIFIC RESPONSES TO CARRY AVIAN-TRANSMITTED PATHOGENS, INFORMING THE PUBLIC HEALTH INTERVENTION AGAINST THOSE PATHOGENS. OUR RECENT FIELD FINDINGS DEMONSTRATE THAT WILD BIRDS FREQUENTLY CARRY CERTAIN BB OSPC GENOTYPES (E.G., OSPC-E, -I, -N) WHICH ARE RARELY FOUND IN PEROMYSCUS. IN CONTRAST, BIRDS LESS OFTEN CARRY GENOTYPES (E.G., OSPC-K) WHICH ARE COMMON IN PEROMYSCUS. THIS IS CONSISTENT WITH OUR LABORATORY FINDINGS IN PEROMYSCUS, OR AMERICAN ROBINS AS A MODEL AVIAN RESERVOIR: OSPC-E-INFECTED ROBINS TRANSMITTED BB TO FED LARVAE MORE EFFICIENTLY THAN OSPC-E-INFECTED PEROMYSCUS, WHEREAS THE OPPOSITE WAS TRUE FOR OSPC-K. THESE FINDINGS HIGHLIGHT THE ROLE OF BIRDS AS A RESERVOIR FOR BB STRAINS THAT ARE RARELY CARRIED BY PEROMYSCUS. IN ADDITION, THEY VALIDATE ROBINS AS A MODEL OF AVIAN RESERVOIR HOST WHICH ALLOWS US TO RECAPITULATE THE FIELD FINDINGS IN A CONTROLLED LABORATORY ENVIRONMENT. USING THIS MODEL, WE FOUND THAT DURING EARLY INFECTION, ROBINS INDUCED ROBUST INFLAMMATORY (E.G., IFNΓ, TNF) AND ANTIBODY RESPONSES TO LESS COMPETENT BIRD GENOTYPES (OSPC-K), BUT ONLY MINIMAL RESPONSES TO BIRD-ADAPTED GENOTYPES (OSPC-E). INTERESTINGLY, ANTIBODY RESPONSES TO OSPC-E OR OSPC-K WERE INDISTINGUISHABLE LATE IN THE INFECTION. ADDITIONALLY, OSPC-E STRAIN ESCAPED ROBIN COMPLEMENT-MEDIATED KILLING MORE EFFICIENTLY THAN OSPC-K STRAIN. THUS, THESE HEIGHTENED IMMUNE RESPONSES WERE ASSOCIATED WITH BB CLEARANCE, IMPLYING THAT MODULATION OF EARLY HOST IMMUNE RESPONSES MAY FACILITATE THE PERSISTENCE OF CERTAIN BB GENOTYPES IN BIRDS. IN THIS PROPOSAL WE ARE TESTING THE HYPOTHESIS THAT WILD BIRDS MAINTAIN CERTAIN BB GENOTYPES BY MODULATING EARLY IMMUNE RESPONSES IN A STRAIN-SPECIFIC MANNER. WE THUS WILL 1) ASCERTAIN THE ROLE OF COMPLEMENT ON SURVIVAL AND PERSISTENCE OF BIRD-ADAPTED BB STRAINS IN BIRDS. 2) DETERMINE THE IMPACT OF DELAYED ANTIBODY RESPONSE ON SURVIVAL OF BIRD-ADAPTED BB STRAINS IN BIRDS. 3) INVESTIGATE THE ROLE OF IMMUNE TOLERANCE ON SURVIVAL AND PERSISTENCE OF BIRD-ADAPTED BB STRAINS IN BIRDS. THIS STUDY WILL DEFINE A NEW PARADIGM IN PATHOGEN MAINTENANCE IN ANIMAL RESERVOIR HOSTS, IDENTIFYING THE IMMUNE MECHANISMS THAT ALLOW WILD BIRDS TO SERVE AS A UNIQUE RESERVOIR OF HUMAN-RELEVANT BB. SUCH KNOWLEDGE WILL ULTIMATELY INFORM INTERVENTION FOR THE TRANSMISSION OF BB AND OTHER BIRD-TRANSMITTED PATHOGENS AND REDUCING HUMAN EXPOSURE TO THOSE PATHOGENS.

LYSYL OXIDASE PROPEPTIDE: BREAST CANCER INHIBITOR

PATERNAL TRANSMISSION ACROSS GENERATIONS OF THE NEGATIVE EFFECTS OF SOCIAL STRESS

ATYPICAL ASTROCYTES IN AGING AND ALZHEIMER'S DISEASE - SUMMARY. ASTROCYTES CONTROL NEUROTRANSMISSION, CONTRIBUTE TO THE BLOOD-BRAIN-BARRIER (BBB), AND SHAPE INFLAMMATORY RESPONSES. IN HEALTHY AGING, MANY ASPECTS OF ASTROCYTE FUNCTION ARE ALTERED BUT WHAT DRIVES AGING-RELATED CHANGES IS NOT WELL UNDERSTOOD. HERE, WE PRESENT EXCITING PRELIMINARY DATA THAT DURING NORMAL AGING, ASTROCYTES TAKE ON A NOVEL PHENOTYPE IN WHICH PROGRESSIVELY MORE ASTROCYTES LOSE THE EXPRESSION OF KEY FUNCTIONAL PROTEINS. WE REFER TO THESE AS ATYPICAL ASTROCYTES (ATAS). ATAS LACK EXPRESSION OF EXCITATORY AMINO ACID TRANSPORTERS (EAATS: GLT-1 AND GLAST), THAT REMOVE GLUTAMATE FROM THE EXTRACELLULAR SPACE, KIR4.1, WHICH MEDIATES EXTRACELLULAR POTASSIUM (K+) BUFFERING, AND AQUAPORIN-4 (AQP-4), WHICH HELPS CLEAR A FROM THE BRAIN. THESE CHANGES OCCUR ON A CELL-BY-CELL BASIS, WITH INDIVIDUAL ASTROCYTES EXPRESSING MINIMAL EAAT, KIR4.1, AND AQP-4, WHILE NEIGHBORING ASTROCYTES REMAIN NORMAL. ATAS DO NOT APPEAR TO BE REACTIVE ASTROCYTES AS THEY LACK ELEVATED GFAP EXPRESSION AND HAVE NORMAL ASTROCYTE MORPHOLOGY. PRELIMINARY IGLUSNFR AND ASTROCYTE ELECTROPHYSIOLOGY DATA SUGGEST THAT GLUTAMATE AND K+ HOMEOSTASIS IS COMPROMISED IN AREAS WHERE ATAS ARE ABUNDANT. WHAT CAUSES ATA TO FORM IS NOT KNOWN, BUT PUBLISHED AND PRELIMINARY STUDIES SUGGEST ATAS ARE ASSOCIATED WITH VASCULAR STRUCTURES AND ARE FOUND IN AREAS OF BLOOD-BRAIN-BARRIER (BBB) COMPROMISE. OUR PRELIMINARY DATA ALSO SUGGESTS THAT ATAS ARE FOUND IN THE AGING HUMAN BRAIN AND ARE MORE ABUNDANT IN THE APPNL-G-F MODEL OF AD, AS COMPARED TO WT MICE. THEREFORE, WE HYPOTHESIZE THAT AGE-ASSOCIATED VASCULAR DYSFUNCTION DRIVES THE FORMATION OF ATAS, DISRUPTING ASTROCYTE FUNCTION AND CONTRIBUTING TO SYNAPTIC AND AD-RELATED PATHOLOGY. ASTROCYTE DYSFUNCTION OCCURS LATE IN AD PROGRESSION, BUT HOW ASTROCYTES CONTRIBUTE TO EARLY AD PATHOLOGY IS NOT WELL UNDERSTOOD. WE SUSPECT ATAS OCCUR EARLY IN AD PROGRESSION AND CONTRIBUTE TO DIVERSE AD DISEASE MECHANISMS. EVIDENCE SUPPORTS THAT ABERRANT GLUTAMATE SIGNALING CONTRIBUTES TO AD PROGRESSION. DISRUPTED AQP-4 EXPRESSION IS A HALLMARK OF AD AND ASSOCIATED WITH REDUCED A CLEARANCE. VASCULAR DYSFUNCTION IS AN AD RISK FACTOR AND ASTROCYTES CONTRIBUTE TO BBB INTEGRITY. TO EXAMINE ATAS IN A MODEL OF AD, WE CHOSE THE APPNL-G-F MICE DUE TO EARLY ONSET OF ELEVATED SOLUBLE A AND PLAQUES OVERLAPPING WITH THE NORMAL DEVELOPMENT OF ATAS, WITHOUT APP OVEREXPRESSION. IF OUR HYPOTHESIS IS CORRECT, ATAS MAY BE A CENTRAL PLAYER IN AGING AND AD-RELATED PATHOLOGIES LINKING VASCULAR DYSFUNCTION TO SYNAPTIC AND A PATHOLOGY. IN THIS PROPOSAL WE WILL DETERMINE 1) WHAT ARE THE MOLECULAR AND CELLULAR PHENOTYPES OF ATAS IN THE AGING AND AD BRAIN?, 2) DO ATAS DISRUPT SYNAPTIC FUNCTION, IONIC HOMEOSTASIS, AND A HANDLING?, AND 3) DOES BBB DYSFUNCTION CONTRIBUTE TO THE GENERATION OF ATAS? WHEN COMPLETE, WE WILL KNOW THE MOLECULAR AND CELLULAR PROPERTIES OF AGE-ASSOCIATED ATAS, THEIR EFFECTS ON ASTROCYTE-MEDIATED HOMEOSTASIS, AND THEIR RELATIONSHIP WITH BBB DYSFUNCTION. IF ATAS MEDIATE ASTROCYTE-NEURON DYSFUNCTION CAUSED BY AGE-RELATED VASCULAR PATHOLOGY, IT WILL REPRESENT AN ENTIRELY NEW AVENUE TO PURSUE FOR TREATING AD AND OTHER AGE-RELATED NEUROLOGICAL DISEASE.

ROLE OF PROTEIN KINASE C IN ISOFORMS IN BILE FORMATION AND CHOLESTASIS

PRODUCTS OF THE TRANSFORMING GENES OF POLYOMAVIRUS

BEHAVIORAL AND MECHANISTIC DISSECTION OF A COGNITIVE THALAMO-CORTICAL NETWORK

MOLECULAR ANALYSIS OF FUNCTIONAL NEURAL CIRCUITS