Duquesne University Of The Holy Spirit

EMERGENCY FINANCIAL AID GRANT TO INSTITUTIONS UNDER CORONAVIRUS AID RELIEF, AND ECONOMIC SECURITY ACT (CARES)

EMERGENCY FINANCIAL AID GRANT TO STUDENTS UNDER CORONAVIRUS AID RELIEF, AND ECONOMIC SECURITY ACT (CARES)

SPECIAL EDUCATION RESEARCH PROGRAM

ADVANCED NURSE EDUCATION-SEXUAL NURSE ASSAULT EXAMINER PROGRAM

COMMUNITY PROJECT FUNDING/CONGRESSIONALLY DIRECTED SPENDING - CONSTRUCTION

PNEUMOCYSTIS JIROVECII TARGETED ANTIOPPORTUNISTIC AGENTS

ROLES OF HOST FACTORS IN VIRAL REPLICATION COUPLED PROCESSES - HERPES SIMPLEX VIRUS IS A PREVALENT PATHOGEN THAT INFECTS THE MAJORITY OF THE HUMAN POPULATION. VIRAL DNA REPLICATION IS AN ESSENTIAL STEP IN THE VIRUS LIFE CYCLE AND CAN BE TARGETED BY ANTIVIRAL TREATMENTS. HERPESVIRAL DNA REPLICATION IS COUPLED TO OTHER VIRAL PROCESSES INCLUDING TRANSCRIPTION, DNA RECOMBINATION, AND DNA REPAIR. HOWEVER, THERE ARE CRITICAL GAPS IN OUR CURRENT KNOWLEDGE OF THE MOLECULAR MECHANISMS BY WHICH THESE PROCESSES ARE COORDINATED AND REGULATED ON THE VIRAL DNA. THE RECENT DEVELOPMENT OF PROTEOMIC APPROACHES TO STUDY PROTEIN ASSOCIATION WITH REPLICATION FORKS HAS ENABLED AN IN DEPTH LOOK AT THIS FUNDAMENTAL PROCESS WITHIN CELLS. IN ADDITION TO THE VIRAL REPLICATION MACHINERY, SELECT HOST CHROMATIN REMODELING, TRANSCRIPTION, DNA MODIFYING, AND DNA REPAIR FACTORS ASSOCIATE WITH HSV-1 REPLICATION FORKS. OUR LONG-TERM GOAL IS TO UNCOVER HOW HSV-1 SUBVERTS HOST CELLULAR FACTORS TO REPLICATING VIRAL DNA TO COORDINATE VIRAL DNA SYNTHESIS WITH DNA DAMAGE RESPONSE PATHWAYS, DNA REPAIR, AND TRANSCRIPTION IN VIVO. IN THE PROPOSED AIMS, PROTEOMIC AND GENOME-WIDE ASSAYS WILL BE USED TO 1) INVESTIGATE MECHANISMS THAT COUPLE THE VIRAL REPLICATION MACHINERY TO CELLULAR DNA REPAIR PATHWAYS, 2) DETERMINE HOW CELLULAR FACTORS MEDIATE THE REPLICATION COUPLED SWITCH TO ACTIVATE LATE GENE TRANSCRIPTION, AND 3) DISSECT HOW REPLICATION FORK ASSOCIATED FACTORS REGULATE VIRAL DNA TOPOLOGY AND GENOME INTEGRITY. INNOVATIVE APPROACHES WILL BE EMPLOYED TO DEFINE THE FUNCTIONS OF HOST PROTEINS DURING VIRAL DNA REPLICATION. HOW VIRAL MODIFICATION OF CELLULAR FACTORS ALTERS CELLULAR DNA REPLICATION AND REPAIR WILL ALSO BE INVESTIGATED. HOST PROTEINS THAT ARE EXPLOITED DURING VIRAL DNA REPLICATION CAN BE TARGETED BY ANTIVIRAL THERAPIES. FURTHERMORE, INSIGHT INTO HOW VIRAL REPLICATION IS COORDINATED WITH THE DNA DAMAGE RESPONSE, VIRAL CHROMATIN, AND TRANSCRIPTION REGULATION WILL AID IN THE DEVELOPMENT OF EFFECTIVE HSV-1 BASED GENE THERAPY APPROACHES AND ONCOLYTIC VECTORS.

RENOVATION OF SCIENTIFIC RESEARCH LABORATORY FACILITIES AT DUQUESNE UNIVERSITY

PURINE SYNTHESIS INHIBITORS WITH SELECTIVE FOLATE RECEPTOR TUMOR TRANSPORT

NURSING WORKFORCE DIVERSITY

PARTNERSHIPS FOR PREVENTION: A PLAN FOR MANAGING STUDENT STRESS, ANXIETY, AND PAIN THROUGH INTERACTIVE?MEDIA.

SDCI DATA: IMPROVEMENT: JAVA GRAPHICAL AUTHORSHIP ATTRIBUTION PROGRAM (JGAAP)

WATER SOLUBLE ANTIMITOTICS THAT CIRCUMVENT RUMOR RESISTANCE

NURSE FACULTY LOAN PROGRAM

LONG-ACTING NONOPIOID ANALGESIC (LANA) NANOMEDICINE FOR RAPID, SINGLE-DOSE, SUSTAINED PAIN CONTROL AND REHABILITATION SUPPORT AFTER NEUROMUSCULOSKELETAL INJURY. NEW AWARD.

CRCNS: COMPUTATIONAL AND EXPERIMENTAL STUDY OF DOPAMINE AND SEROTONIN TRANSPORTER

PHOTOACOUSTIC DETECTION, CAPTURE, AND ANALYSIS OF CIRCULATING MELANOMA CELLS

THE ROLE OF PHOSPHOLIPID TURNOVER IN MEMBRANE PROTEIN FUNCTION

NURSE EDUCATION, PRACTICE, QUALITY AND RETENTION - VETERANS BACHELOR OF SCIENCE IN NURSING PROGRAM

NEURO-IMMUNO MODULATING ANALGESIC (NIMA) NANOMEDICINE PLATFORM FOR TREATMENT OF DIABETIC NEUROPATHY

A PARTNERSHIP IN NEUROSCIENCE EDUCATION

TOWARD FIELD-READY PARATRANSGENESIS FOR MALARIA: BACTERIAL STRAIN OPTIMIZATION AND MICROBIOTA INTERACTIONS - PROJECT SUMMARY/ABSTRACT MALARIA IS A DISEASE CAUSED BY PROTOZOAN PARASITES (PLASMODIUM SPP.) THAT ARE TRANSMITTED TO HUMANS BY FEMALE MOSQUITOES OF THE GENUS ANOPHELES. THERE ARE NEARLY 250 MILLION NEW CASES OF MALARIA EVERY YEAR, AND OVER 600,000 PEOPLE DIE FROM THE DISEASE WHILE MILLIONS OF OTHERS ARE SEVERELY DEBILITATED (DATA FROM 2021). ABOUT HALF OF THE HUMAN POPULATION IS AT RISK OF CONTRACTING MALARIA, AND ITS RANGE MAY SPREAD AS GLOBAL WARMING ACCELERATES. A LONG-TERM RESEARCH GOAL OF HIGH PRIORITY IN THE BIOMEDICAL HEALTH SCIENCES THEREFORE IS TO CREATE NEW METHODS OF COMBATING MALARIA TO COMPLEMENT CURRENT METHODS OF CONTROL, NAMELY INSECTICIDES TO KILL MOSQUITO VECTORS AND DRUGS TO KILL PARASITES IN INFECTED PEOPLE. THE OVERALL OBJECTIVE OF THIS MULTI-PI PROPOSAL IS TO ENGINEER PARATRANSGENIC BACTERIAL STRAINS THAT CAN INTERFERE WITH THE ABILITY OF MOSQUITOES TO TRANSMIT MALARIA PARASITES. WE WILL ACCOMPLISH THIS BY LEVERAGING OUR COMBINED EXPERTISE IN BACTERIAL GENETICS AND VECTOR MICROBIAL ECOLOGY TO OVERCOME EXISTING CHALLENGES THAT MAKE CURRENTLY AVAILABLE PARATRANSGENIC STRAINS UNSUITABLE FOR FIELD RELEASE. MORE SPECIFICALLY, WE WILL ENGINEER PARATRANSGENIC STRAINS OF ASAIA BOGORENSIS THAT CONTAIN NO ANTIBIOTIC RESISTANCE GENES, THAT ARE HIGHLY RESISTANT AGAINST HORIZONTAL TRANSFER TO NON-TARGET SPECIES, AND THAT SECRETE COMBINATIONS OF EFFECTOR PROTEINS AT SUFFICIENT QUANTITIES FOR OPTIMAL ANTI-PLASMODIUM PERFORMANCE IN VIVO (AIM 1). WE WILL ALSO CONCURRENTLY EXAMINE THE IMPACT OF MICROBIOTA COMPOSITION AND PARATRANSGENESIS SYSTEM COMPONENTS ON THE OVERALL FITNESS AND ANTI-PLASMODIUM PERFORMANCE OF PARATRANSGENIC STRAINS IN MOSQUITOES COLONIZED BY BACTERIAL COMMUNITIES DERIVED FROM INDIVIDUALS COLLECTED IN MALARIA ENDEMIC REGIONS OF WEST AFRICA (AIM 2). TOGETHER, THESE EXPERIMENTS WILL ALLOW US TO IDENTIFY FIELD-READY STRAINS THAT ARE LIKELY TO PERSIST AFTER INTRODUCTION INTO NATURAL MOSQUITO POPULATIONS, WITH LITTLE TO NO IMPACT ON RESIDENT MICROBIAL COMMUNITIES AND MINIMAL NEED FOR COSTLY REINTRODUCTION STRATEGIES. THEY WILL ALSO SIGNIFICANTLY ADVANCE OUR FUNDAMENTAL UNDERSTANDING OF HOW INDIVIDUAL BACTERIAL STRAINS COLONIZE AND PERSIST IN MOSQUITO HOSTS–A TOPIC OF BROAD INTEREST GIVEN THE ABILITY OF MOSQUITO-ASSOCIATED BACTERIA TO SHAPE MOSQUITO PHENOTYPES IMPORTANT FOR PATHOGEN TRANSMISSION.

THE OVERALL PURPOSE OF WATERQ2 IS TO SUPPORT BASIN STAKEHOLDERS, INCLUDING THE LIMPOPO WATERCOURSE COMMISSION (LIMCOM), TO IMPROVE GOVERNANCE AROUND WATER RESOURCES MANAGEMENT AND WATER SECURITY IN THE BASIN. ACTIVITIES TO BE CONDUCTED UNDER THE AWARD INCLUDE COLLECTING AND SHARING HYDROLOGIC DATA, TRAINING STUDENTS, RESOURCE MANAGERS, AND DECISION MAKERS, FACILITATING NETWORKING AND COMMUNICATION AMONG INSTITUTIONS, AND ESTABLISHING AND SUPPORTING DEDICATED TECHNICAL RESOURCES IN THE LIMPOPO RESILIENCE LAB.

NURSE FACULTY LOAN PROGRAM

REGENERATIVE MEDICINE PARTNERSHIP IN EDUCATION (PHASE I*

INVESTIGATION OF FRAGILE X MENTAL RETARDATION PROTEIN INTERACTIONS WITH THE MIRNA PATHWAY.

CYANOBACTERIAL NATURAL PRODUCTS TO TREAT COMORBID PAIN AND DEPRESSION

IN VITRO ANALYSIS OF THE EFFECTS OF ACUTE AND CHRONIC PHTHALATE EXPOSURES ON LEYDIG CELL TESTOSTERONE PRODUCTION, AND THE MOLECULAR MECHANISMS INVOLVED

PAIN AND NEURODEGENERATIVE UNDERGRADUATE RESEARCH EXPERIENCES: INTERACTING WITH COMMUNITY PARTNERS TO BUILD SPECIALIZED AND ENHANCED NEUROLOGIC DISEASE PROGRAMS FOR UNDERGRADUATES.

A SOCIAL MEDIA PERSONALIZED NORMATIVE FEEDBACK INTERVENTION FOR HEAVY DRINKING STUDENTS

PARATRANSGENESIS FOR MALARIA USING ASAIA SP. BACTERIA

ALPHA FOLATE RECEPTOR MEDIATED GARFTASE INHIBITORS AS SELECTIVE ANTITUMOR AGENTS

MODELS FOR NITRATE REDUCTASES AND RELATED ENZYMES

ANTITUMOR ANTIMITOTICS THAT REVERSE TUMOR RESISTANCE

RESUSCITATION BY ENDOTHELIAL STABILIZATION AND TARGETED OXYGEN RESCUE (RESTOR) PLATFORM FOR VASCULARIZED COMPOSITE ALLOTRANSPLANTATION

COMPREHENSIVE PROGRAM

NURSE FACULTY LOAN PROGRAM

NITRILE-CONTAINING DECALINS IN MEDICINE

EVIDENCE-BASED MENTAL HEALTH SERVICES FOR DISTRESSED POST-9/11 MILITARY FAMILY CAREGIVERS

NURSE FACULTY LOAN PROGRAM

GENOMIC COMPETENCIES FOR NURSES FROM THEORY TO APPLICATION: AN ONLINE LONG COURSE - PROJECT SUMMARY/ABSTRACT THE OVERARCHING GOALS OF GENOMIC COMPETENCIES FOR NURSES FROM THEORY TO APPLICATION: AN ONLINE LONG COURSE, ARE TO CREATE A TRAINING OPPORTUNITY BASED ON THE ESSENTIAL GENETIC AND GENOMIC COMPETENCIES FOR NURSES WITH GRADUATE DEGREES TAILORED TO DOCTORAL-LEVEL NURSING FACULTY AND STUDENTS AND TO IMPROVE NURSES’ GENETIC LITERACY AND GENOMIC SCIENCE LITERACY TO BENEFIT PATIENT/POPULATION HEALTH CARE OUTCOMES, PARTICULARLY THOSE FROM UNDERREPRESENTED MINORITIES (URM), THROUGH RESEARCH, EVIDENCE-BASED PRACTICE, EDUCATION, AND ADVOCACY. SPECIFIC AIMS OF THE ONLINE LONG COURSE ARE TO: INCREASE LITERACY IN GENOMICS AMONG DOCTORAL-LEVEL NURSES AND FACULTY TO IMPROVE THE DELIVERY OF HEALTHCARE IN THE ERA OF GENOMIC MEDICINE; 2) PROVIDE A FOUNDATIONAL INTRODUCTION TO THE GENETIC BASIS OF DISEASE, HEALTH RISK ASSESSMENT, EPIGENETICS, AND PERSONALIZED HEALTHCARE WITH AN EMPHASIS ON THE ASSOCIATED ETHICAL IMPLICATIONS OF GENETIC AND GENOMIC ADVANCEMENTS; 3) [IDENTIFY OPPORTUNITIES FOR DOCTORAL LEVEL NURSES’ AND FACULTY TO APPLY GENOMIC MEDICINE INTO RESEARCH, TEACHING, AND CLINICAL PRACTICE; AND 4) PREPARE DOCTORAL-LEVEL NURSES AND FACULTY TO ASSIMILATE STATE-OF-THE-SCIENCE GENETICS AND RELATED ETHICAL ISSUES INTO THEIR RESEARCH, TEACHING, AND CLINICAL PRACTICE WITH A FOCUS ON PATIENTS FROM URM. [BASED ON THE INTEGRATED MULTIMODAL MODEL OF ONLINE EDUCATION], THIS SELF-PACED ONLINE LONG COURSE BEGINS WITH [AN OPTIONAL] PRIMER MODULE ON THE BASICS OF GENETICS AND GENOMICS, FOLLOWED BY SIX TOPIC-SPECIFIC LEARNING MODULES BASED ON THE [ESSENTIAL COMPETENCIES, EACH LED BY A TEAM OF EXPERTS. A COMPREHENSIVE EVALUATION PLAN INCLUDES PRE- AND POST-COURSE ASSESSMENTS FOR STUDENTS, AS WELL AS ONGOING QUALITY IMPROVEMENT.] PARTICIPANTS WILL BE ABLE TO EARN A CONTINUING EDUCATION (CE) CERTIFICATE SPECIFYING NURSING CONTINUING EDUCATION UNITS UPON COMPLETION OF A COURSE SATISFACTION SURVEY AND POST-COURSE ASSESSMENTS. [AN ADVISORY COMMITTEE WILL PROVIDE OVERSIGHT AND ASSISTANCE IN ENSURING THAT COURSE CONTENT STAYS UP TO DATE OVER A 5-YEAR PERIOD. THROUGH THIS PROJECT, A DIVERSE GROUP OF NURSING DOCTORAL STUDENTS AND FACULTY WILL GAIN EXPERTISE RELATED TO THE MISSION OF NHGRI, RESULTING IN SIGNIFICANT BENEFITS FOR NURSING SCIENCE, THE NURSING WORKFORCE, AND ULTIMATELY, FOR PATIENTS. OF NOTE, THIS COURSE CAN PROCEED IN THE CURRENT, UNPREDICTABLE ENVIRONMENT DUE TO COVID- 19 BECAUSE IT WILL BE DELIVERED REMOTELY BY LEADERS IN ONLINE NURSING EDUCATION.]

NOVEL, P. JIROVECII SPECIFIC ANTIPNEUMOCYSTIS AGENTS

DOPAMINE TRANSPORTER STRUCTURE AND FUNCTION

SCHOLARSHIPS FOR ACADEMICALLY TALENTED AND FINANCIALLY DISADVANTAGED UNDERGRADUATE AND GRADUATE STUDENTS

CAREER: CHARACTERIZATION OF VOCAL FOLD VASCULAR LESIONS BIOMECHANICS USING COMPUTATIONAL MODELING -THIS FACULTY EARLY CAREER DEVELOPMENT (CAREER) GRANT WILL ADVANCE FUNDAMENTAL UNDERSTANDING OF THE VASCULAR LESIONS OF HUMAN VOCAL FOLDS. THESE LESIONS REFER TO DILATED BLOOD VESSELS IN THE FOLD?S TISSUE AND ARE PARTICULARLY COMMON IN PROFESSIONS WITH HIGH VOICE USAGE, SUCH AS EDUCATORS, PUBLIC SPEAKERS, AND SINGERS. THE PRESENCE OF VASCULAR LESIONS AND THEIR POTENTIAL RUPTURE AFFECT THE ABILITY OF THE TISSUE TO VIBRATE NORMALLY, WHICH SEVERELY DISRUPTS SPEECH AND LEADS TO VOCAL FATIGUE. HOWEVER, THE UNDERLYING MECHANISMS OF LESION GROWTH AND FATIGUE RESULTING FROM THIS CONDITION REMAIN UNCERTAIN. THERE IS THUS A SIGNIFICANT NEED TO INVESTIGATE THE EFFECTS OF VASCULAR LESIONS ON THE PHONATION PROCESS. THIS PROJECT WILL DEVELOP PREDICTIVE COMPUTATIONAL MODELS OF COUPLED AERODYNAMICS, HEMODYNAMICS, AND SOLID MECHANICS TO ACCOUNT FOR THESE LESIONS, THEIR PROGRESSION, AND THE CORRESPONDING VOICE FATIGUE. THE RESULTANT FRAMEWORK WILL ENABLE IMPROVEMENTS IN BIOMECHANICAL MODELS OF THE HUMAN LARYNX, WHILE SUCH MODELS ARE ALSO BEING CONSIDERED FOR POTENTIAL USE IN SURGICAL INTERVENTIONS, ENHANCEMENT IN PREVENTION OF VOICE DISORDERS, AND EXPLORING ISSUES RELATED TO VOICE TRAINING. ALONG WITH THE DEVELOPMENT AND DISSEMINATION OF TECHNICAL TOOLS, THE AWARD WILL ALSO SUPPORT THE EDUCATION AND TRAINING OF UNDERREPRESENTED MINORITIES, EXPANSION THROUGH VIRTUAL AND ON-SITE OUTREACH ACTIVITIES TO INSPIRE APPRECIATION OF PHONATION BIOMECHANICS WITHIN A GENERAL AUDIENCE AND CONNECT WITH INTERESTED PATIENTS, AS WELL AS INTERACTION WITH PRE-COLLEGIATE STUDENTS FROM MARGINALIZED BACKGROUNDS THROUGH AN ANNUAL SUMMER WORKSHOP. THE SPECIFIC GOAL OF THE RESEARCH IS TO ANALYZE THE THREE-WAY INTERACTION BETWEEN THE VASCULAR LESION, POROVISCOELASTIC VOCAL FOLD TISSUE, AND GLOTTAL AIRFLOW, TO ILLUSTRATE THE BIOMECHANICAL CHARACTERISTICS OF THE TISSUE AND QUANTIFY METRICS THAT ARE HYPOTHESIZED TO BE ASSOCIATED WITH VOCAL FATIGUE. THEREFORE, THE RESEARCH OBJECTIVES OF THIS PROJECT INCLUDE: (1) DEVELOPING A FULLY COUPLED MULTI-COMPONENT FLUID-POROELASTIC STRUCTURE INTERACTION MODELING APPROACH INTEGRATING THE TURBULENT GLOTTAL AIRFLOW AND PERMEABLE FOLD TISSUE IN PRESENCE OF VASCULAR LESIONS TO ASSESS VOICE FATIGUE INDICATORS, (2) CREATING A COMPUTATIONAL SOLVER FOR MODELING THE LESION PROGRESSION IN THE FORM OF THE PRESSURE-DRIVEN CRACK FILLED WITH BLOOD PROPAGATING IN THE POROELASTIC TISSUE TO EXPLORE THE SIGNIFICANCE OF PHONATION CONDITIONS, AND (3) QUANTIFYING THE UNCERTAINTY IN THE MODEL PREDICTIONS USING A MONTE-CARLO TYPE SIMULATION APPROACH TO EVALUATE HOW VARIOUS PHYSICAL PARAMETERS AND MORPHOLOGICAL FEATURES AFFECT THE FOLD?S BIOMECHANICS AND LESION PROPAGATION. THIS PROJECT WILL ENABLE THE PI TO ADVANCE THE KNOWLEDGE BASE IN MECHANICS AND COMPUTATIONAL SIMULATION, ESTABLISHING THE FOUNDATION FOR HER LONG-TERM CAREER IN SPEECH BIOMECHANICS. THIS AWARD REFLECTS NSF'S STATUTORY MISSION AND HAS BEEN DEEMED WORTHY OF SUPPORT THROUGH EVALUATION USING THE FOUNDATION'S INTELLECTUAL MERIT AND BROADER IMPACTS REVIEW CRITERIA.- SUBAWARDS ARE NOT PLANNED FOR THIS AWARD.

SINGLE AGENTS WITH DESIGNED COMBINATION CHEMOTHERAPY POTENTIAL

DELIVERY OF MITOCHONDRIA USING EXTRACELLULAR VESICLES AS A NOVEL THERAPY FOR ALS

THE RECIPIENT SHALL PERFORM A COORDINATED RESEARCH AND DEVELOPMENT PROGRAM CARRIED OUT IN ACCORDANCE WITH THE STATEMENT OF WORK ENTITLED "NEOCARE PLAT

MRI: ACQUISITION OF A TANDEM MASS SPECTROMETER FOR 'OMICS RESEARCH

CAREER: CHEMISTRY WITH SIMPLE TETRAHEDRAL BUILDING BLOCKS: SYNTHESIS AND STUDY OF BULK AND NANOCRYSTALLINE DIAMOND-LIKE SEMICONDUCTORS WITH NOVEL O

CAREER: ATOM TRANSFER RADICAL ADDITION AND CYCLIZATION REACTIONS IN THE PRESENCE OF CATALYTIC AMOUNTS OF COPPER COMPLEXES

DIFFERENTIALLY EXPRESSED GENES IN MALE AND FEMALE DRG DURING PAIN AND PAIN-RELIEF; ISOFORM SPECIFIC CELLULAR EXPRESSION OF RNAS - THE OBJECTIVES OF THE PROPOSED RESEARCH INCLUDE 1) TO DEFINE THE DIFFERENTIALLY EXPRESSED RNA SPLICE ISOFORMS OF ATF3 RESPONSIBLE FOR THE SEX-SPECIFIC DIFFERENCES IN PAIN AND PAIN-RELIEF AND DEVELOP A MODEL FOR THEIR INVOLVEMENT IN THE ASSOCIATED MOLECULAR SIGNALING, AND 2) TO PROVIDE RIGOROUS TRAINING TO UNDERGRADUATE RESEARCH SCHOLARS ABOUT PAIN RESEARCH. NERVE INJURY CREATES A DYNAMIC DIALOG BETWEEN GLIA, INFILTRATING IMMUNE CELLS AND NEURONS. IN RESPONSE TO THE MILIEU OF CYTOKINES, THE PERIPHERAL NEURONS BECOME HYPERSENSITIVE, WHICH THE CENTRAL NERVOUS SYSTEM INTERPRETS AS PAIN. THIS ENVIRONMENT CAUSES CHANGES IN GENE EXPRESSION LEADING TO CHRONIC HYPERSENSITIVITY, PERSISTING EVEN AFTER HEALING. WHILE ACUTE HYPERSENSITIVITY IS AN IMPORTANT COMPONENT OF THE NOCICEPTIVE SIGNALING OF INJURY, DISRUPTION OF THIS PROCESS CAN CAUSE PROTRACTED OR DEBILITATING PAIN, LEADING SOME PATIENTS TO OPIOIDS FOR RELIEF, AND THE POSSIBILITY OF EXPERIENCING OPIOID USE DISORDER. HERE, WE PROPOSE TO DEVELOP A MORE COMPREHENSIVE UNDERSTANDING OF THE TRANSCRIPTION FACTORS THAT ARE DIFFERENTIALLY EXPRESSED IN THE RAT DORSAL ROOT GANGLIA DURING NEUROINFLAMMATION ASSOCIATED WITH HYPERSENSITIVITY AND PAIN, AND THAT ARE DIFFERENTIALLY EXPRESSED BETWEEN SEXES DURING PAIN-RELIEF. RAT NEUROPATHIC PAIN RESULTING FROM SURGICAL CHRONIC CONSTRICTION OF THE SCIATIC NERVE, CAUSES HYPERSENSITIVITY OVER THE SAME TIME COURSE AND QUANTITATIVELY TO THE SAME DEGREE IN BOTH SEXES. HOWEVER, WHEN TREATED WITH A SINGLE MICRO-DOSE OF A NANOTHERAPEUTIC CONTAINING 0.24 MG/KG OF CELECOXIB, WE FIND THAT MALES ACHIEVE MULTI-DAY PAIN RELIEF EQUAL TO PRE-SURGICAL BASELINE, WHILE FEMALES RECEIVING THE SAME TREATMENT ACHIEVE ONLY PARTIAL RELIEF. THIS INDICATES THAT THE UNDERLYING BIOLOGY OF THE NEUROINFLAMMATORY RESPONSE THAT IS REACTING TO THE NSAID IS DIFFERENT IN MALES AS COMPARED TO FEMALES. USING A HIGHER SINGLE DOSE OF CELECOXIB PER NANODROPLET (2.4 MG/KG), WE HAVE FOUND THAT MALES AND FEMALES CAN ACHIEVE THE SAME RELIEF. UNDER THE CONDITIONS OF EQUAL RELIEF, OUR NEXTSEQ (ILLUMINA) AND SEPARATELY REVIO LONG-READ (PACBIO) RNA SEQUENCING OF THE DORSAL ROOT GANGLIA REVEALED DIFFERENTIAL EXPRESSION AND ALTERNATIVE RNA SPLICING BETWEEN THE NEUROINFLAMMATORY STATE AND RELIEF FOR MALES VERSUS FEMALES. THIS COLLECTION OF SEXUALLY DIMORPHIC AND DIFFERENTIALLY EXPRESSED GENES INCLUDES GENES OF THE DRUGGABLE PROTEOME. THE PRIMARY TARGET OF OUR PROPOSED ANALYSIS IS ATF3, A CYCLIC AMP RESPONSE ELEMENT BINDING PROTEIN (CREB) TRANSCRIPTION FACTOR RESPONSIVE TO NERVE INJURY AND NERVE REGENERATION. RESEARCH BY OTHERS SHOW THAT ATF3 HAS DISTINCT FUNCTIONS DEPENDING ON THE PROTEIN ISOFORM PRODUCED BY DIFFERENT MRNA SPLICE VARIANTS. WITH TEAMS OF UNDERGRADUATE RESEARCH SCHOLARS, WE PROPOSE TO EXPLORE THE CELL SPECIFIC AND SPLICE ISOFORM SPECIFIC EXPRESSION OF ATF3 MRNAS IN THE NEURONS, GLIA AND INFILTRATING IMMUNE CELLS DURING PAIN, DURING PAIN RELIEF AND DURING TISSUE REGENERATION THROUGH THE USE OF MULTI-COLOR FLUORESCENT IN SITU HYBRIDIZATION FOR BOTH MALES AND FEMALES. OTHER CANDIDATE GENES THAT WE WILL STUDY INCLUDE THE TRANSCRIPTION FACTORS FOS AND NR1D1, AND THE DYNAMIN-LIKE GTPASE MX1, EACH EXHIBITING SEXUALLY DIMORPHIC AND DIFFERENTIAL EXPRESSION.

EXAMINING GLYCINE RECEPTOR'S INTRACELLULAR DOMAIN BY CROSSLINKING-MASS SPECTROMETRY - PROJECT SUMMARY. WHILE HIGH-RESOLUTION STRUCTURAL DATA ARE AVAILABLE FOR MEMBERS OF THE PENTAMERIC LIGAND-GATED ION CHANNEL (PLGIC) SUPERFAMILY IN MEMBRANE-MIMETIC ENVIRONMENTS, THE STRUCTURE OF THE INTRACELLULAR DOMAIN (ICD) OF THESE RECEPTORS IN LIPID BILAYERS REMAINS UNRESOLVED. OUR AIMS ARE TO CONDUCT CROSSLINKING MASS SPECTROMETRIC STUDIES (CXMS) TO COMPLEMENT CURRENT METHODS AND CHARACTERIZE THE STRUCTURE OF FULL-LENGTH A1 GLYCINE RECEPTORS (GLYRS) IN RECONSTITUTED BILAYERS DIFFERENT ALLOSTERIC STATES, WITH A PARTICULAR FOCUS ON THE ICD. SPECIFIC AIM 1 WILL USE CXMS TO INTERROGATE THE PROTEIN STRUCTURE OF THE ICD AROUND SINGLE SITES OF ATTACHMENT OF A VARIABLE-LENGTH PHOTOACTIVATABLE PROTEIN-PROTEIN CROSSLINKERS DISTRIBUTED OVER THE FULL LENGTH OF THE ICD AS A FUNCTION OF GLYR ALLOSTERY. SPECIFIC AIM 2 WILL USE CXMS TO EXAMINE LIPID-PROTEIN INTERACTIONS AS A FUNCTION OF ALLOSTERY USING LIPID CROSSLINKERS WITH THEIR RESPECTIVE PHOTOACTIVATABLE MOIETIES AT DIFFERENT DEPTHS OF THE BILAYER, WITH A PARTICULAR FOCUS ON THE CLOSE ASSOCIATIONS OF THE ICD WITH THE LIPID BILAYER. TOGETHER, THE CXMS APPROACHES USED IN EACH AIM WILL PROVIDE INSIGHT INTO THE STRUCTURE OF THIS PREVIOUSLY UNRESOLVED DOMAIN AND COMPLEMENT HIGH RESOLUTION STUDIES CONDUCTED IN MEMBRANE-MIMETIC ENVIRONMENTS.

RNA HOMODIMERIZATION STRAND DISPLACEMENT PATHWAYS TO EXTENDED DUPLEXES: ATOMISTIC DETAILS FOR A MECHANISTIC PARADIGM TO IDENTIFY UNIQUE ANTIVIRAL TARGETS FOR CURRENT AND EMERGING VIRAL PANDEMICS - PROJECT SUMMARY KISSING COMPLEXES (KC) AND EXTENDED DUPLEXES (ED) REPRESENT DYNAMIC RNA STRUCTURES WHOSE INTERCONVERSION IS AN EXAMPLE OF STRAND DISPLACEMENT REACTIONS THAT HAS BEEN IMPLICATED IN PLAYING VITAL ROLES IN SEVERAL VIRUSES, INFLUENCING A BROAD SPECTRUM OF BIOCHEMICAL PROCESSES INCLUDING GENOME PACKAGING, VIRAL RECOMBINATION, AND HOST-PATHOGEN INTERACTIONS. HOWEVER, THE STRUCTURAL, DYNAMIC, AND ENERGETIC DETAILS ON HOW THESE INTERCONVERSIONS OCCUR ARE VIRTUALLY UNKNOWN YET ARE VITAL IN OUR NOVEL APPROACH OF IDENTIFYING AND CHARACTERIZING PREVIOUSLY UNCONSIDERED META-STABLE PATHWAY STATES TO INSPIRE FUTURE ANTIVIRAL AND DRUG RESISTANCE DEVELOPMENT. OVERCOMING SIGNIFICANT CHALLENGES THAT HAMPER MEANINGFUL MODELLING OF RNA AND DIMERS, AND ASSOCIATED INTERCONVERSION PATHWAYS NECESSITATE JUDICIOUS CHOICE OF COMPUTATIONAL TECHNIQUES AND INTEGRATION WITH EXPERIMENTAL DATA ACROSS PHYSIOLOGICALLY RELEVANT TIMESCALES. OUR OVERARCHING HYPOTHESIS IS THAT BY LEVERAGING THE LIMITED KINETIC AND THERMODYNAMIC DATA REPORTED ON RNA TRANSITION PATHWAY SYSTEMS, INCLUDING THE HUMAN IMMUNODEFICIENCY VIRUS 1 (HIV-1) DIMER INITIATION SITE (DIS) AND MODEL COMPLEXES BASED ON THE BACTERIAL E. COLI DSRA-RPOS RNA-MRNA REGULATORY COMPLEX, A GENERAL PARADIGM WILL BE DEVELOPED FOR OTHER KNOWN RNA DIMERIZATION SYSTEMS, SUCH AS SARS-COV, SARS-COV-2, HCV, AND FUTURE EMERGING RNA VIRUSES REQUIRING NOVEL ANTIVIRAL THERAPIES. TO ADDRESS OUR HYPOTHESIS, WE FIRST EMPLOY A UNIQUE APPROACH TO ESTABLISH THE UNBIASED STRUCTURE AND DYNAMICS OF RNA STRUCTURES REPRESENTING BOTH PATHWAY ENDPOINTS OF EACH STRAND DISPLACEMENT REACTION, SUCH AS KC TO ED (AIM I). CONFIDENCE IN STRUCTURAL PREDICTIONS FOR SYSTEMS WITHOUT EXPERIMENTAL STRUCTURES IS ENGENDERED BY COMPARING COMPUTATIONS AGAINST HIV-1 DIS CRYSTALLOGRAPHIC STRUCTURES. WE NEXT APPLY A MINIMUM ENERGY PATHWAY TECHNIQUE WITH AND WITHOUT PROTEIN CHAPERONES TO IDENTIFY META-STABLE STATES (AIM II). RELIABILITY OF THE METHOD IS EVALUATED AGAINST THE KINETIC AND THERMODYNAMIC DATA REPORTED FOR THE KC TO ED INTERCONVERSION FOR THE E. COLI DSRA-RPOS RNA-MRNA REGULATORY COMPLEX. FINALLY, AS A PROOF OF CONCEPT, WE WILL SCREEN RNA-BINDING MOLECULES AND ANTISENSE OLIGONUCLEOTIDES AGAINST IDENTIFIED META-STABLE INTERMEDIATES ALONG THE PATHWAYS (AIM III). ALIGNED WITH NIH/R15 GOALS, WE WILL TRAIN UNDERGRADUATES TO UNDERSTAND THE CAPABILITIES, LIMITATIONS, AND ERRORS OF EXPERIMENTAL AND COMPUTATIONAL CHEMISTRY TO CRAFT ULTIMATELY A SEAMLESS RESEARCH APPROACH. OUR TRAINING OBJECTIVE IS TO DELIVER A QUALITY RESEARCH EXPERIENCE THAT MOTIVATES UNDERGRADUATES TO ACHIEVE THEIR HIGHEST POTENTIAL AND BEST PREPARE THEM FOR SCIENTIFIC RESEARCH AND DISCOVERY. THE INTENT IS TO ATTRACT AND RETAIN THE NATION’S DIVERSE STUDENT TALENT POOL, HAVING THE CONSEQUENCE OF ENRICHING AND DIVERSIFYING THE U.S. WORKFORCE BY ADDING EXPERTS IN THE FIELD OF BIOMEDICAL CHEMISTRY. THE EXPECTED SCIENTIFIC OUTCOMES ARE TO UNLOCK NOVEL PHYSICAL INSIGHTS INTO STRAND DISPLACEMENT REACTIONS AND PROVIDE A FOUNDATION FOR TARGETED DRUG DESIGN AND THERAPEUTIC INTERVENTIONS FOR DRUG RESISTANCE OF HIV-1, SARS-COV2, AND HCV VIRUSES OF CURRENT

CAREER: REGULATION OF CARGO SELECTION AND UBIQUITINATION BY PROTEIN TRAFFICKING ADAPTORS

EXPANDING AND REFINING THE APPLICATION-BASED SERVICE-LEARNING PEDAGOGY

UNIVERSITY CENTER 2011

NANOIMAGING FOR NONINVASIVE MONITORING OF DONOR AND RECIPIENT IMMUNE SYSTEM CONTRIBUTION TO ACUTE AND CHRONIC REJECTION IN VCA. NEW AWARD.

2018 HPF SAT - DUQUESNE UNIVERSITY

CAMPUS SANE NETWORK PROGRAM

NUTRITIONAL ENDODERM, A NOVEL TISSUE IN A DIRECT DEVELOPING FROG

CMMI-EPSRC: A NOVEL MULTIFUNCTIONAL PLATFORM TO STUDY CELL AND NUCLEAR MECHANOSENSING -CELLS CAN DETECT AND INTERPRET MECHANICAL SIGNALS, TURNING THEM INTO CHEMICAL SIGNALS THAT IMPACT IMPORTANT BIOLOGICAL PROCESSES SUCH AS TISSUE DEVELOPMENT, REGENERATION, AND DISEASES. HOWEVER, HOW CELLS SENSE AND RESPOND TO MECHANICAL FORCES ARE NOT WELL UNDERSTOOD. THIS PROJECT AIMS TO EXPLORE HOW CELLS RESPOND TO MECHANICAL SIGNALS AND HOW THEY PASS THESE SIGNALS TO NEIGHBORING CELLS, HELPING US TO BETTER UNDERSTAND HOW MECHANICAL FORCES SHAPE OUR BODIES. THIS PROJECT WILL ENABLE TRAINING OF A DIVERSE GROUP OF RESEARCHERS AND INVOLVING THEM INTERNATIONAL PARTNERSHIPS. THE PROJECT ALSO INVOLVES EFFORTS TO RECRUIT MORE WOMEN AND UNDERGRADUATE STUDENTS TO PARTICIPATE IN SCIENCE AND ENGINEERING, AND OUTREACH ACTIVITIES TO SHARE INFORMATION ABOUT BIOMEDICAL DEVICES AND THEIR USE IN IMPROVING HUMAN HEALTH. MECHANICAL FORCES PLAY A CRITICAL ROLE IN MANY PHYSIOLOGICAL PROCESSES INCLUDING CELL ADHESION, MIGRATION, PROLIFERATION, DIFFERENTIATION AND MORPHOGENESIS DURING TISSUE FORMATION AND ORGANOGENESIS IN DEVELOPMENT. HOWEVER, HOW MECHANICAL CUES ARE TRANSMITTED TO NEIGHBORING CELLS AND WHETHER SUCH INTERCELLULAR MECHANOTRANSDUCTION LEADS TO NUCLEAR REORGANIZATION AND CHANGES IN GENE EXPRESSION IN ADJACENT CELLS REMAINS ELUSIVE. USING MICROFLUIDICS, 3D IMAGING, AND MACHINE LEARNING, THIS PROJECT AIMS TO DEVELOP A HIGH THROUGHPUT MECHANOBIOLOGY PLATFORM CAPABLE OF APPLYING PHYSIOLOGICALLY RELEVANT MECHANICAL FORCES TO SINGLE CELLS WITH HIGH SPATIOTEMPORAL RESOLUTION AND IMAGING REAL-TIME CELL RESPONSE TO ELUCIDATE MOLECULAR MECHANISMS OF INTRA- AND INTERCELLULAR MECHANOTRANSDUCTION. THE PLATFORM WILL ADVANCE OUR UNDERSTANDING OF HOW CELLS RESPOND TO MECHANICAL STIMULI AND HELP REVEAL MOLECULAR MECHANISMS THAT UNDERLIE THE TRANSMISSION OF FORCES FROM THE CELL PERIPHERY TO THE NUCLEUS AND NEIGHBORING CELLS. THIS RESEARCH WAS FUNDED UNDER THE NSF DIRECTORATE FOR ENGINEERING - UKRI ENGINEERING AND PHYSICAL SCIENCES RESEARCH COUNCIL LEAD AGENCY OPPORTUNITY (ENG-EPSRC), NSF 20-510. THIS AWARD REFLECTS NSF'S STATUTORY MISSION AND HAS BEEN DEEMED WORTHY OF SUPPORT THROUGH EVALUATION USING THE FOUNDATION'S INTELLECTUAL MERIT AND BROADER IMPACTS REVIEW CRITERIA.

DEVELOPMENT OF QUATERNARY DIAMOND-LIKE SEMICONDUCTORS FOR INFRARED NONLINEAR OPTICAL APPLICATIONS

ACCOUNTS OF CARE PARTNERSHIPS WITH WOUNDED, ILL OR INJURED SERVICE MEMBERS

ADVANCED NURSE EDUCATION-SEXUAL NURSE ASSAULT EXAMINER PROGRAM

CC* NETWORKING INFRASTRUCTURE: A HIGH-PERFORMANCE SCIENCE DMZ AND DEDICATED RESEARCH NETWORK FOR DUQUESNE UNIVERSITY

NURSE FACULTY LOAN PROGRAM

NITRATE ENHANCED MICROBIAL CR(VI) REDUCTION NEW AWARDEE

MYELINATION AND RESILIENCE AGAINST LIMBIC ALPHA-SYNUCLEINOPATHY - ABSTRACT LEWY BODY DISORDERS ARE HYPOTHESIZED TO INVOLVE THE SPREAD OF A-SYNUCLEIN AGGREGATES THROUGH THE CENTRAL NEURAXIS, WITH CRANIAL NERVES I (PRIMARY OLFACTORY NERVE) AND X (DORSAL VAGAL NERVE) AS THE MOST LIKELY PERIPHERAL ENTRY POINTS. THE OLFACTORY AND DORSAL VAGAL NERVES ARE UNMYELINATED, AS ARE MANY OF THE NEURONAL GROUPS MOST VULNERABLE TO A-SYNUCLEINOPATHY (E.G., NIGROSTRIATAL EFFERENTS). BASED ON THESE OBSERVATIONS, UNMYELINATED NEURONS WERE HYPOTHESIZED TO BE SELECTIVELY VULNERABLE TO LEWY PATHOLOGY, BUT THIS IDEA WAS LARGELY OVERLOOKED FOR THE LAST TWO DECADES. AS A RESULT, THE RELATIONSHIP BETWEEN THE DEGREE OF MYELINATION AND RESILIENCE AGAINST A-SYNUCLEINOPATHY IS STILL POORLY UNDERSTOOD. THE PROCESS OF MYELINATION IS KNOWN TO LIE UNDER THE CONTROL OF MICROGLIAL CELLS IN NEURODEVELOPMENT, BUT THIS LINK ALSO REMAINS OPEN FOR EXPLORATION IN LEWY BODY DISORDERS. TO FILL THESE GAPS, WE WILL LEVERAGE OUR NEW SEX-STRATIFIED, IN VIVO MODEL OF LIMBIC A-SYNUCLEINOPATHY, IN A SERIES OF STUDIES APPROPRIATELY SCALED FOR THE R15 MECHANISM AND SPECIFICALLY DESIGNED FOR PH.D., PHARM.D., AND UNDERGRADUATE STUDENTS IN THE SCHOOL OF PHARMACY AT DUQUESNE UNIVERSITY. THE FOLLOWING CENTRAL HYPOTHESIS WILL BE TESTED WITH A FULL-FACTORIAL EXPERIMENTAL DESIGN: MYELINATION IS LINKED TO RESILIENCE AGAINST LIMBIC A-SYNUCLEINOPATHY AND IS MODIFIED BY MICROGLIA/MACROPHAGES. IN AIM 1, OUR TEAM WILL TEST THE SUBHYPOTHESIS THAT MARKERS OF MYELINATION IN PROJECTION FIBERS OF THE OLFACTORY BULB, SUCH AS THE INTRABULBAR ANTERIOR COMMISSURE AND LATERAL OLFACTORY TRACTS, ARE INVERSELY CORRELATED WITH BEHAVIORAL, HISTOLOGICAL, AND BIOCHEMICAL DISEASE-RELATED OUTCOMES IN PREFORMED FIBRIL-INFUSED MICE. IN AIM 2, WE WILL TEST THE SUBHYPOTHESIS THAT HYPOMYELINATION OR DEMYELINATION AMPLIFIES LIMBIC A-SYNUCLEINOPATHY AT THE HISTOLOGICAL AND BIOCHEMICAL LEVELS AND WORSENS BEHAVIOR DEFICITS. IN THIS AIM, MICE HETEROZYGOUS FOR MYELIN BASIC PROTEIN (MBP) WILL BE INFUSED WITH PREFORMED FIBRILS IN THE OLFACTORY BULB, AS THESE MICE DISPLAY SUBTLE HYPOMYELINATION-RELATED DEFICITS WITHOUT SHORTENED LIFESPANS OR SEVERE BEHAVIOR DEFICITS. A SEPARATE COHORT OF FIBRIL-INFUSED MICE WILL BE FED THE COPPER-CHELATOR CUPRIZONE IN THE DIET, AS THIS COMPOUND IS KNOWN TO DEMYELINATE THE ANTERIOR COMMISSURE AND LATERAL OLFACTORY TRACTS. IN AIM 3, WE WILL TEST THE SUBHYPOTHESIS THAT MICROGLIA/MACROPHAGES IMPROVE MYELINATION AND TEMPER LIMBIC A-SYNUCLEINOPATHY IN AGING MICE. THE CSF1R ANTAGONIST PLX5622 WILL BE FED TO FIBRIL-INFUSED, AGING MICE TO DEPLETE BRAIN CELLS OF MYELOID ORIGIN. THIS DIET WILL BE FOLLOWED BY PLX5622 WITHDRAWAL IN ONE COHORT TO REJUVENATE THE AGING MICROGLIAL NICHE. WE EXPECT THAT MICROGLIAL/MACROPHAGE DEPLETION WILL WORSEN MYELIN CONDITION AND LEWY BODY DISEASE-RELATED OUTCOMES, WHEREAS MICROGLIAL/MACROPHAGE REPOPULATION WILL IMPROVE THOSE MEASURES. THE PROPOSED TECHNICAL APPROACHES CAN BE COMPLETED BY PH.D., PHARM.D., AND UNDERGRADUATE STUDENTS AT DUQUESNE. STUDENTS IN MY LAB HAVE EARNED FIRST-AUTHORSHIP ON 19 PAPERS, INCLUDING 4 PAPERS WITH UNDERGRADUATE OR PHARM.D. STUDENTS AS FIRST AUTHORS. REGARDLESS OF THE DIRECTION OF THE OUTCOMES, THE PROPOSED WORK WILL SHED LIGHT ON THE POTENTIAL LINK BETWEEN MYELINATION AND LEWY-RELATED PATHOLOGIES, WHILE STUDENTS WILL BE TRAINED IN THE CONDUCT AND DISSEMINATION OF BIOMEDICAL RESEARCH ON PRECLINICAL ANIMAL MODELS OF LIMBIC LEWY BODY DISEASE.

THE INTEGRATION OF LABORATORY DATA WITH COMPUTATIONAL 3-D MODELING TO ANALYZE THE ROLE OF THE CENTRAL AMYGDALA IN NEUROPATHIC PAIN - PROJECT SUMMARY/ABSTRACT NEUROPATHIC PAIN IMPACTS THE LIVES OF MILLIONS OF INDIVIDUALS WORLDWIDE. UNDERSTANDING THE MECHANISMS THAT DRIVE THE DEVELOPMENT AND MAINTENANCE OF NEUROPATHIC PAIN IS CRITICAL TO THE ADVANCEMENT OF NEXT GENERATION THERAPEUTIC STRATEGIES. IN THE CONTEXT OF NERVE INJURY, ONE BRAIN AREA THAT MAY CONTRIBUTE TO PAIN IS THE CENTRAL NUCLEUS OF THE AMYGDALA (CEA). EVIDENCE FROM HUMAN PATIENTS AND ANIMAL MODELS SHOWS SHORT AND LONG-TERM CHANGES IN THE AMYGDALA MAY CONTRIBUTE TO THE OVERALL PATHOLOGIC STATE. AN EXPLOSION OF CELL-TYPE SPECIFIC OPTOGENETIC, CHEMOGENETIC, AND PHYSIOLOGICAL APPROACHES HAS PROVIDED UNPRECEDENTED CELLULAR ACCESS TO THE CEA IN THE CONTEXT OF INJURY. A MAJOR CHALLENGE FOR THE FIELD IS DETERMINING HOW TO INTEGRATE DATA FROM DIFFERENT APPROACHES AND LABORATORIES TO UNDERSTAND THE AMYGDALA’S CONTRIBUTION TO NOCICEPTION AND PAIN. WE RECENTLY DEVELOPED THE FIRST COMPUTATIONAL MODEL OF THE CEA IN THE CONTEXT OF PAIN USING REAL-WORLD CELL-TYPE DATA. THIS MODEL, BUILT WITH PHYSIOLOGICAL DATA AND VALIDATED AGAINST IN VIVO RESULTS, PROVIDES A ROBUST FRAMEWORK TO STUDY THE INTERACTIONS BETWEEN DIFFERENT CELL TYPES AND THEIR COLLECTIVE CONTRIBUTIONS TO THE DEVELOPMENT OF PAIN. OUR MODEL OF THE CEA MARKS A MAJOR STEP FORWARD IN THE STUDY OF NEUROPATHIC PAIN, BUT AT THE SAME TIME THE MODEL IS STILL PRIMITIVE IN ITS ASSUMPTIONS. THE MODEL REPRESENTS THE CEA IN 2-DIMENSIONAL SPACE AND FAILS TO ACCURATELY CAPTURE THE COMPLEX 3-DIMENSIONAL (3-D) STRUCTURAL PROPERTIES OF THE CEA AND ITS SUBNUCLEI THAT LIKELY DRIVE PRONOCICEPTIVE AND ANTINOCICEPTIVE OUTPUTS FROM THE CEA. THE OBJECTIVE OF THIS PROPOSAL IS TO UTILIZE EXISTING AND NEW WET-LAB DATA TO BUILD A PROOF-OF-CONCEPT 3-D MODEL OF PAIN-RELATED NEURONS IN THE CEA THAT ACCOUNTS FOR SPATIAL AND CELL-TYPE HETEROGENEITY AND DETERMINE THE EXTENT TO WHICH THE MODEL CAN PREDICT IN VIVO RESULTS. OUR CENTRAL HYPOTHESIS IS THAT THE 3-D DISTRIBUTION OF TWO SPECIFIC CELL TYPES IN THE CEA INFLUENCES THE APPROPRIATE BEHAVIORAL RESPONSES IN THE CONTEXT OF NEUROPATHIC INJURY AND THAT THIS DISTRIBUTION CAN BE MODELED TO PRODUCE NOVEL INSIGHTS INTO THE CEA’S ROLE IN THE DEVELOPMENT OF CHRONIC NOCICEPTION. WE WILL USE AN AGENT-BASED COMPUTATIONAL MODEL TO DESCRIBE THE PHYSIOLOGICAL AND MORPHOLOGICAL PROPERTIES OF INDIVIDUAL NEURONS IN THE CEA AND THEIR INTERACTIONS WITH ONE ANOTHER. THIS APPROACH WILL ALLOW US TO CAPTURE COMPLEXITY WITHIN THE CEA SYSTEM WHILE REMAINING ACCESSIBLE TO UNDERGRADUATE STUDENTS, INCLUDING THOSE NEW TO PROGRAMMING. THE COMPUTATIONAL MODEL, WHICH WILL BE PUBLICLY AVAILABLE AND OPEN SOURCE, WILL INCLUDE A GRAPHICAL USER INTERFACE THAT CAN BE ACCESSED BY ANY RESEARCHER TO COMPLETE IN SILICO EXPERIMENTS PRIOR TO DEVOTING THE TIME AND RESOURCES TO COSTLY IN VIVO EXPERIMENTS. BOTH COMPUTATIONAL AND WET-LAB EXPERIMENTS ARE INCORPORATED IN THIS PROPOSAL WITH A FOCUS ON INVOLVEMENT OF UNDERGRADUATE STUDENTS TO BOLSTER THEIR DEVELOPMENT AS RIGOROUS, INTERDISCIPLINARY, AND THOUGHTFUL BIOMEDICAL RESEARCHERS.

MOLECULAR BASIS OF ADAPTATION OF SEMINAL PROTEINS OF HUMANS AND OTHER PRIMATES

OPTICAL, ELECTRICAL AND MAGNETIC PROPERTIES OF MULTI-CATION DIAMOND-LIKE SEMICONDUCTORS: INTRICATE SEMICONDUCTOR SYSTEMS FOR PHYSICAL PROPERTY TUNING

DEVELOPMENT-ASSOCIATED LINEAR CHROMOSOME SEGREGATION IN STREPTOMYCES - PROJECT SUMMARY STREPTOMYCES ARE UBIQUITOUS FILAMENTOUS SPORULATING SOIL BACTERIA, IMPORTANT IN THE ENVIRONMENT BECAUSE THEY DEGRADE AND RECYCLE THE NUTRIENTS LOCKED IN MANY RECALCITRANT NATURAL POLYMERS IN THE SOIL (E.G., CELLULOSE AND CHITIN) AND PRODUCE THE MAJORITY OF A WIDE RANGE OF BIOLOGICALLY ACTIVE COMPOUNDS THAT ARE USED EXTENSIVELY IN HUMAN AND VETERINARY MEDICINE (E.G., ANTIBIOTIC, ANTIVIRAL, ANTICANCER, ANTITUMOR, ANTIFUNGAL, IMMUNOSUPPRESSANT AND ANTHELMINTIC PHARMACEUTICALS). STREPTOMYCES ARE ALSO WELL KNOWN AS ONE OF THE MAJOR PRODUCERS OF THE COMPOUNDS THAT GIVE SOIL ITS CHARACTERISTIC EARTHY ODOR. THESE ORGANISMS HAVE LARGE LINEAR GENOMES. LITTLE IS KNOWN ABOUT THE ARCHITECTURE OF THE LINEAR CHROMOSOME WITHIN THE STREPTOMYCES SPORE AND THE MECHANISMS WHICH GOVERN ITS DEVELOPMENT-ASSOCIATED GENOME SEGREGATION AND NUCLEOID CONDENSATION DURING SPORE FORMATION ARE POORLY UNDERSTOOD. THE ULTIMATE GOAL FROM THE PROPOSED BASIC RESEARCH IS TO HAVE A BETTER UNDERSTANDING OF THE NOVEL CELLULAR PROCESSES OF THESE DISTINCTIVE ORGANISMS OF TREMENDOUS MEDICAL IMPORTANCE. THE UNUSUAL MYCELIAL LIFE CYCLE AND LINEAR STRUCTURE OF THE STREPTOMYCES GENOME ARE LIKELY TO REQUIRE SOME UNIQUE SOLUTIONS TO THE FUNDAMENTAL PROBLEMS OF GENOME SEGREGATION AND CONDENSATION. THE FIRST SPECIFIC AIM OF THE PROPOSAL IS TO CHARACTERIZE A NOVEL SMALL COILED-COIL PROTEIN THAT IS EXCLUSIVE TO THIS GROUP OF ORGANISMS. A GENETIC APPROACH WAS USED TO PROVIDE EVIDENCE THAT THIS PROTEIN IS INVOLVED IN DEVELOPMENT-ASSOCIATED GENOME SEGREGATION. A PROXIMITY-LABELING APPROACH, WITH A PROMISCUOUS BIOTIN LIGASE FUSION, IS BEING USED TO IDENTIFY PROTEINS THAT INTERACT WITH THIS NOVEL PROTEIN IN VIVO. ALANINE-SCANNING AND RANDOM PCR-DIRECTED MUTAGENESES ARE BEING USED TO IDENTIFY RESIDUES IMPORTANT FOR PROTEIN-PROTEIN INTERACTION WITH ONE KNOWN BINDING PARTNER. THE SECOND SPECIFIC AIM IS TO CHARACTERIZE TYPE VII SECRETION SYSTEM ATPASE PROTEINS. IN ADDITION TO THEIR FUNCTIONS IN PROTEIN SECRETION, THE ATPASE PROTEINS ARE MOONLIGHTING IN DEVELOPMENT-ASSOCIATED SEGREGATION AND NUCLEOID CONDENSATION. A GENETIC APPROACH WILL BE USED TO DISSECT THE FIRST TYPE VII SECRETION ATPASE TO IDENTIFY THE REGION(S) NEEDED FOR GENOME SEGREGATION. A GENETIC APPROACH WILL ALSO BE USED TO DETERMINE THE PARTS OF BOTH TYPE VII SECRETION ATPASES TO IDENTIFY THE REGIONS NECESSARY FOR CORRECT NUCLEOID CONDENSATION IN THE SPORE. MUTANTS LACKING GENES ENCODING BOTH TYPE VII SECRETION ATPASES HAVE GENOMES ORGANIZED AGAINST THE SPORE PERIPHERY (DOUGHNUT-SHAPED) INSTEAD OF BEING CONDENSED AS AN ELLIPSOID NUCLEOID IN THE CENTER OF THE SPORE.

FUNCTIONS OF HISTONES AND CHROMATIN REMODELING COMPLEXES IN PRODUCTIVE HSV-1 INFECTION

RESCUING MYELINATION IN VIRAL INFECTIONS OF THE JUVENILE BRAIN - PROJECT SUMMARY VIRUSES ARE WELL-ESTABLISHED CAUSES OF CENTRAL NERVOUS SYSTEM (CNS) DISEASE IN THE MOST VULNERABLE POPULATIONS, PARTICULARLY IN THE YOUNG AND IMMUNOCOMPROMISED. DURING CNS INFECTION, THE IMMUNE RESPONSE CAN INADVERTENTLY CAUSE NEUROPATHOLOGY, RESULTING IN NEURONAL DEATH AND DEMYELINATION. MOUSE MODELS OF VIRAL INFECTION HAVE SERVED AS A VALUABLE TOOL FOR DISSECTING MECHANISMS OF DEMYELINATING DISEASE IN THE ADULT BRAIN, AND A RICH BODY OF LITERATURE HAS REVEALED A COMPLEX ROLE FOR THE IMMUNE RESPONSE IN DEMYELINATION. HOWEVER, WE KNOW LITTLE ABOUT HOW VIRUSES DISRUPT MYELINATION IN CHILDHOOD, WHEN BOTH NEURONS, OLIGODENDROCYTES (OLS), AND IMMUNE CELLS ARE ACTIVELY MATURING. THUS, TRUE MYELIN RESTORATION REMAINS AN ELUSIVE THERAPEUTIC GOAL IN DEMYELINATING DISEASES AT ALL AGES. THE LONG-TERM GOAL IS TO IDENTIFY MECHANISMS TO SUPPORT THE PRESERVATION AND REPAIR OF BRAIN CELLS IN THE VERY YOUNG. THE OVERALL OBJECTIVE OF THIS PROJECT IS TO EVALUATE THE RESPONSE OF OLIGODENDROCYTE PRECURSOR CELLS (OPCS), WHICH ULTIMATELY GIVE RISE TO MYELINATING OLS, DURING A VIRAL INFECTION IN THE DEVELOPING BRAIN. USING A JUVENILE MOUSE MODEL OF NEURON-RESTRICTED VIRUS INFECTION, WHERE OPCS/OLS ARE BYSTANDERS TO THE ANTIVIRAL IMMUNE RESPONSE, WE HAVE FOUND THAT OPCS EXPAND DRAMATICALLY DURING INFECTION, AND INFILTRATING ADAPTIVE IMMUNE CELLS ARE PRIMARY DRIVERS OF THIS OPC RESPONSE. THE GENERAL HYPOTHESIS IS THAT OPCS ARE SPURRED TO PROLIFERATE BY INFILTRATING B CELLS DURING A JUVENILE INFECTION, BUT THAT FULL-FLEDGED OPC DIFFERENTIATION IS ULTIMATELY IMPEDED BY VIRALLY-INFECTED NEURONS. THE GENERAL HYPOTHESIS WILL BE TESTED VIA THE FOLLOWING THE SPECIFIC AIMS: (1) DETERMINE THE PROTECTIVE ROLE OF JUVENILE IMMUNE CELLS IN PROMOTING OPC PROLIFERATION; AND (2) DEFINE THE ROLE OF OPC MATURATION IN RECOVERY FROM DEMYELINATION DURING A JUVENILE INFECTION. IN AIM 1, WE WILL USE GENETIC AND MOLECULAR APPROACHES TO DEFINE HOW OPC PROLIFERATION AND MATURATION ARE REGULATED BY SUBSETS OF B CELLS OVER THE COURSE OF A JUVENILE INFECTION. IN AIM 2, WE WILL ASSESS HOW VIRALLY-INFECTED NEURONS REGULATE THE DIFFERENTIATION OF NEWLY-GENERATED OPCS USING IN VIVO AND IN VITRO APPROACHES. THE EXPECTED OUTCOMES ARE THAT WE WILL DEFINE CELLULAR AND MOLECULAR INTERACTIONS THAT DIRECT OPC FATE DURING A JUVENILE VIRAL INFECTION. COLLECTIVELY, THESE RESULTS ARE EXPECTED TO HAVE A SIGNIFICANT IMPACT BY PROVIDING A BASIS FOR THE DEVELOPMENT OF THERAPIES TO PRESERVE OR RESTORE MYELINATION IN THE YOUNG BRAIN. THIS RESEARCH ALIGNS WITH NIND'S MISSION BY GENERATING FUNDAMENTAL INSIGHTS INTO INTERACTIONS BETWEEN THE BRAIN AND IMMUNE CELLS, AND BY APPLYING THAT NEW KNOWLEDGE TO REDUCE THE BURDEN OF NEUROLOGICAL DISEASE IN THE MOST VULNERABLE POPULATIONS.

MULTI-STAKEHOLDER DETERMINANTS OF MEDICARE DIABETES PREVENTION PROGRAM IMPLEMENTATION AND PARTICIPATION - PROJECT SUMMARY/ABSTRACT NEARLY HALF OF US ADULTS AGE = 65 (> 24 MILLION) HAVE PREDIABETES, WHICH IS OFTEN A PRECURSOR TO TYPE 2 DIABETES MELLITUS (T2DM) AND ASSOCIATED CARDIOVASCULAR (CV) DISEASES AND MORTALITY. TO ADDRESS THIS PUBLIC HEALTH BURDEN, THE CENTERS FOR MEDICARE AND MEDICAID SERVICES ENACTED COVERAGE OF THE MEDICARE DIABETES PREVENTION PROGRAM (MDPP) IN 2018. BASED ON THE NATIONAL DIABETES PREVENTION PROGRAM (NDPP), THE MDPP IS AN EVIDENCE-BASED (EB) LIFESTYLE INTERVENTION THAT HOLDS GREAT PROMISE, BUT IS OFTEN UNAVAILABLE AND GREATLY UNDERUTILIZED. REASONS FOR LACK OF ACCESS AND USE REMAIN UNIDENTIFIED, LEAVING A CRITICAL NEED TO DETERMINE THE INDIVIDUAL, ORGANIZATIONAL, AND CONTEXTUAL FACTORS AMONG PROGRAM SUPPLIERS, OLDER ADULTS, AND HEALTHCARE PROVIDERS THAT ARE AFFECTING MDPP AVAILABILITY AND USE. THE OBJECTIVE FOR THIS R15 REAP APPLICATION IS TO DETERMINE THE DIVERSE FACTORS, PROCESSES, FACILITATORS, AND BARRIERS AFFECTING MDPP IMPLEMENTATION AND USE, WHILE PROVIDING AN OPPORTUNITY TO STIMULATE RESEARCH AT DUQUESNE UNIVERSITY. WITHOUT IDENTIFYING THESE FACTORS, IMPLEMENTATION STRATEGIES TO REDUCE BARRIERS AND PROMOTE FACILITATORS OF THE MDPP CANNOT BE READILY ENACTED. WE WILL PURSUE THREE SPECIFIC AIMS USING THE CONSOLIDATED FRAMEWORK FOR IMPLEMENTATION RESEARCH (CFIR) TO GUIDE A MULTI-LEVEL, CONVERGENT MIXED METHODS INVESTIGATION OF THE MDPP. AIM 1: IDENTIFY PERCEIVED FACILITATORS AND BARRIERS TO IMPLEMENTATION AND USE OF THE MDPP IN A NATIONAL SAMPLE OF PROGRAM SUPPLIERS AND OLDER ADULTS. WE WILL CONDUCT ~15 WEB-BASED OR PHONE INTERVIEWS WITH EACH STAKEHOLDER GROUP: MDPP SUPPLIERS, NDPP SUPPLIERS, MDPP PARTICIPANTS, AND ELIGIBLE NON-PARTICIPANTS. WE WILL ALSO ADMINISTER AN ESTABLISHED SURVEY TO 64 MDPP AND 64 NDPP SUPPLIERS TO ASSESS THE INNER SETTING OF THE CFIR. AIM 2: DETERMINE CURRENT PRACTICES AND RECRUITMENT STRATEGIES MDPP SUPPLIERS USE TO RAISE AWARENESS OF THE MDPP AND ENROLL OLDER ADULTS. WE WILL FIRST ADMINISTER THE PROGRAM ADOPTION AND IMPLEMENTATION STRATEGIES ELEMENTS OF A WEB-BASED SURVEY TO A NATIONAL SAMPLE OF 80 MDPP SUPPLIERS, AND IDENTIFY THE STRATEGIES YIELDING THE HIGHEST ENROLLMENT OF OLDER ADULTS. AIM 3: DETERMINE THE INDIVIDUAL AND ORGANIZATIONAL FACTORS PROMOTING OR INHIBITING REFERRAL OF ELIGIBLE OLDER ADULTS TO THE MDPP AMONG A NATIONAL SAMPLE OF HEALTHCARE PROVIDERS. WE WILL ADMINISTER A WEB- BASED VERSION OF THE HEALTHCARE PROVIDER PREDIABETES SURVEY TO 200 PHYSICIANS AND ADVANCED PRACTICE PROVIDERS; WE WILL ALSO INTERVIEW A SUBSAMPLE OF PROVIDERS (~30) TO GATHER IN-DEPTH QUALITATIVE DATA. DATA FROM AIMS 1, 2, AND 3 WILL BE TRIANGULATED, OR INTEGRATED, USING THE CFIR AS THE GUIDING FRAMEWORK. RESULTS OF THE PROPOSED RESEARCH ARE ESSENTIAL TO INFORM THE DEVELOPMENT OF IMPLEMENTATION INTERVENTIONS FOR MULTIPLE STAKEHOLDER GROUPS, TO SCALE THE MDPP TO A LEVEL THAT MEANINGFULLY REDUCES THE BURDEN OF T2DM AND CV DISEASE. THE MDPP IS THE FIRST MEDICARE-COVERED DISEASE PREVENTION PROGRAM, BUT COVERAGE IS NOT YET PERMANENT. ENSURING SUCCESS OF THE MDPP WILL PRESERVE THIS BENEFIT FOR MILLIONS OF AT-RISK OLDER ADULTS AND HELP DRIVE PAYOR COVERAGE FOR OTHER PREVENTION PROGRAMS IN THE FUTURE. OUR TEAM’S LONG-TERM GOAL IS TO REDUCE THE BURDEN OF LIFESTYLE-DRIVEN CV DISEASE BY FACILITATING IMPLEMENTATION OF EB INTERVENTIONS.

CAS: COMPUTATIONAL DATA-DRIVEN METAL-FREE CATALYSTS DISCOVERY FOR SMALL MOLECULE ACTIVATION AND CONVERSION -IN THIS PROJECT, FUNDED BY THE CHEMICAL STRUCTURE, DYNAMICS & MECHANISMS-B PROGRAM OF THE CHEMISTRY DIVISION, JINGYUN YE OF THE DEPARTMENT OF CHEMISTRY AND BIOCHEMISTRY AT DUQUESNE UNIVERSITY AIMS TO DESIGN AND DISCOVER ENERGY-SAVING, ENVIRONMENTALLY FRIENDLY, AND LOW-COST METAL-FREE CATALYSTS FOR SMALL MOLECULE ACTIVATION. SMALL MOLECULE CONVERSIONS SUCH AS THE CONVERSION OF CARBON DIOXIDE TO USEFUL CHEMICALS AND FUELS HAVE THE POTENTIAL TO REDUCE RELIANCE ON FOSSIL CARBON SOURCES AND BUILD A MORE RENEWABLE CARBON CYCLE. THE APPROACH TAKEN HERE IS BASED ON FRUSTRATED LEWIS PAIRS (FLPS). THIS PROJECT AIMS TO CONSTRUCT AN OPEN ACCESS FLP DATABASE AND TO COMBINE QUANTUM MECHANICAL MODELING WITH DATA SCIENCE AND MACHINE LEARNING TO ACCELERATE THE DISCOVERY OF NOVEL FLPS WITH TARGETED CATALYTIC REACTIVITY FOR SMALL MOLECULE ACTIVATION AND CONVERSION. THE PROPOSED RESEARCH WILL HAVE SIGNIFICANT EDUCATIONAL AND RESEARCH OPPORTUNITIES FOR THE NEXT GENERATION OF RESEARCHERS IN THE CROSS-DISCIPLINARY FIELDS OF CHEMISTRY, COMPUTATIONAL MODELING, MATERIALS SCIENCE, CATALYSIS, DATA SCIENCE, AND ARTIFICIAL INTELLIGENCE, WITH A PARTICULAR FOCUS ON PROMOTING THE PARTICIPATION OF MEMBERS OF UNDERREPRESENTED GROUPS AND WOMEN IN SCIENCE. FRUSTRATED LEWIS PAIRS ARE THE SIMPLE COMBINATION OF A BULKY LEWIS ACID AND A BULKY LEWIS BASE THAT ARE STERICALLY PRECLUDED FROM REACTING WITH EACH OTHER. THE UNQUENCHED LEWIS ACID AND LEWIS BASE SITES ARE AVAILABLE TO ACCEPT AND DONATE ELECTRON DENSITY, RESPECTIVELY, PROVIDING A UNIQUE ROUTE TO THE ACTIVATION AND CATALYTIC CONVERSION OF SMALL MOLECULES. THE OVERALL RESEARCH GOAL OF THIS PROJECT IS TO REVEAL THE STRUCTURE-ACTIVITY RELATIONSHIPS OF FLPS FOR SMALL MOLECULE ACTIVATION AND THE DESIGN OF NOVEL AND EFFICIENT METAL-FREE CATALYSTS FOR ENERGY CONVERSION AND ENVIRONMENTAL CONCERNS VIA THE COMBINATION OF DENSITY FUNCTIONAL THEORY, DATA SCIENCE, AND MACHINE LEARNING. THE PROJECT OBJECTIVES ARE TO: (1) CONSTRUCT AN OPEN-ACCESS FLPS DATABASE THAT CONTAINS STRUCTURAL, ELECTRONIC, AND ENERGETIC DATA OF FLPS AND THEIR ACTIVITY TOWARD SMALL MOLECULE ACTIVATION; (2) IDENTIFY THE STRUCTURE-ACTIVITY RELATIONSHIPS OF FLPS FOR CARBON DIOXIDE HYDROGENATION AND ALKYNE SEMI-HYDROGENATION USING MACHINE LEARNING; AND (3) DESIGN FLPS WITH TARGETED PROPERTIES FOR SMALL MOLECULE ACTIVATION AND CATALYSIS VIA DEEP LEARNING. THIS AWARD REFLECTS NSF'S STATUTORY MISSION AND HAS BEEN DEEMED WORTHY OF SUPPORT THROUGH EVALUATION USING THE FOUNDATION'S INTELLECTUAL MERIT AND BROADER IMPACTS REVIEW CRITERIA.- SUBAWARDS ARE NOT PLANNED FOR THIS AWARD.

REPOPULATION OF THE MICROGLIA/MACROPHAGE NICHE IN EXPERIMENTAL LEWY BODY DISEASE - LEWY BODY DISORDERS ARE A FAMILY OF NEURODEGENERATIVE CONDITIONS CHARACTERIZED BY DEPOSITION OF THE ABUNDANT SYNAPTIC PROTEIN, Α-SYNUCLEIN, IN INSOLUBLE CYTOSOLIC AGGREGATES. THE TWO BRAIN REGIONS MOST VULNERABLE TO Α-SYNUCLEINOPATHY IN EARLY DISEASE STAGES ARE THE OLFACTORY BULB/ANTERIOR OLFACTORY NUCLEUS (OB/AON) OF THE ROSTRAL TELENCEPHALON AND THE DORSOMOTOR VAGAL NUCLEI OF THE CAUDAL BRAINSTEM. WE HAVE INFUSED PREFORMED FIBRILS (PFFS) SYNTHESIZED FROM Α-SYNUCLEIN INTO THE RODENT OB/AON TO INDUCE AGGREGATE FORMATION IN THE LIMBIC FOREBRAIN. LIMBIC Α-SYNUCLEINOPATHY IN OUR MURINE MODEL IS ASSOCIATED WITH IMPAIRMENTS IN SMELL, AFFECT, AND SPATIAL REFERENCE MEMORY. A LARGE BODY OF EXPERIMENTAL EVIDENCE SUPPORTS THE VIEW THAT Α-SYNUCLEINOPATHY IS ASSOCIATED WITH PRION-LIKE SEEDING AND CELL-TO-CELL SPREAD OF THE AGGREGATES THROUGH CIRCUITRY. THUS, THE INTERCELLULAR TRANSFER OF AGGREGATES MAY BE PREVENTED BY ENGULFMENT OF AGGREGATES FROM THE INTERSTITIAL FLUID OR THE EFFEROCYTOSIS OF NEURONS THAT BEAR EARLY SIGNS OF LEWY-RELATED PATHOLOGY. MICROGLIA/MACROPHAGES (MG/MΦ) ARE THE PROFESSIONAL PHAGOCYTES OF THE BRAIN, BUT THEY PLAY COMPLEX ROLES IN DISEASE AND MAY SUFFER PHAGOCYTIC EXHAUSTION WHEN FACED WITH EXCESS Α-SYNUCLEIN. PERHAPS FOR THESE REASONS, MG/MΦ ARE UNABLE TO FULLY PREVENT LEWY BODY DISEASE. HOWEVER, REPOPULATION OF MG/MΦ CAN BE JUMPSTARTED WITH TRANSIENT ADMINISTRATION OF THE ORALLY BIOAVAILABLE CSF1R INHIBITOR, PLX5622. IN OUR PFF MODEL, DIETARY PLX5622 KILLED ~60% OF MG/MΦ, AND UPON PLX5622 WITHDRAWAL, THERE WAS VIGOROUS REPOPULATION OF THE MG/MΦ NICHE AND AN 85% REDUCTION (95% CI 0.02-27.53%) IN Α-SYNUCLEINOPATHIC AGGREGATES IN MALE MICE BY 20 MONTHS OF AGE. UNEXPECTEDLY, TRANSIENT PLX5622 ALSO INCREASED AGGREGATE SIZES IN BOTH SEXES, AND AGGREGATE SIZES WERE POSITIVELY CORRELATED WITH SPATIAL MEMORY. HENCE, LARGER AGGREGATES MAY BE ASSOCIATED WITH LESS PRION-LIKE SEEDING AND DISPERSAL. WE HYPOTHESIZE THAT THE PROBABILITY OF SUCCESSFUL MG/MΦ ENGULFMENT OF Α-SYNUCLEIN AGGREGATES IS BOOSTED AFTER A DEPLETION/REPOPULATION EVENT IN THE PFF MODEL AND ASSOCIATED WITH SUPERIOR SPATIAL MEMORY. PILOT DATA UNEXPECTEDLY REVEAL THAT NEURONS (AND NOT GLIA) HOUSE THE MOST FLUORESCENT PFFS AFTER OB/AON INFUSIONS, WHILE MG/MΦ ENGULF NEURONS HOUSING THE PFFS. IN AIM 1, WE WILL IDENTIFY THE NEURAL CELL TYPE WITH THE HIGHEST PROBABILITY OF HARBORING PFFS, DETERMINE IF THESE CELLS CAN, IN TURN, BE ENGULFED BY MG/MΦ, AND TEST IF BOOSTING MG/MΦ PROLIFERATION BOOSTS THEIR ENGULFMENT CAPACITIES. IN AIM 2, WE WILL ASCERTAIN HOW TRANSIENT PLX5622 EXPOSURE REDUCES Α-SYN AGGREGATE BURDEN IN OUR PFF MODEL. CHANGES IN THE TRANSCRIPTOMES OF DEPLETED/REPOPULATED MG/MΦ IN THE PFF MODEL WILL BE IDENTIFIED BY RNASEQ ON FLOW-SORTED MG/MΦ, WITH A FOCUS ON GENES INVOLVED IN ENDOCYTIC/LYSOSOMAL PROCESSING. THE EXPRESSION OF CANDIDATE GENES WILL BE SUPPRESSED BY MG/MΦ CELL-TARGETED AAV6/TM6-SHRNA, AND WE WILL THEN TEST IF MG/MΦ ENGULFMENT OF Α-SYN AGGREGATES IS LOWERED WHEN LYSOSOMAL PROCESSING IS IMPEDED IN VIVO. IMPACT: IF NEURONS HOUSE THE MOST Α-SYN AGGREGATES AND CANNOT BE ENGULFED BY MG/MΦ IN SUFFICIENT NUMBERS, THIS MAY EXPLAIN WHY DISEASED NEURONS PERSIST LONG ENOUGH TO PROPAGATE LEWY PATHOLOGIES. THIS ALSO IMPLIES THAT NOT ALL CELL LOSS IS DETRIMENTAL. FURTHER, IF DEPLETED/REPOPULATED MG/MΦ CAN ENGULF MORE Α-SYN AGGREGATES, THIS MAY EXPLAIN WHY THEY ARE ABLE TO ALLEVIATE AGGREGATE BURDEN IN OUR PFF MODEL, AND CSF1R BLOCKADE WITH VARIOUS ANTAGONISTS SHOULD CONTINUE TO BE EXPLOITED IN THE BATTLE AGAINST LEWY BODY DISORDERS.

A JOINT COMPUTATIONAL/EXPERIMENTAL BIOMEDICAL SUMMER RESEARCH PROGRAM FOR UNDERGR

INJECTABLE 3D-CLUSTERED HUMAN FIBROBLASTIC RETICULAR CELLS FOR EXPANDING REGULATORY T CELLS - ALLOGRAFT TRANSPLANT REJECTION IS CURRENTLY MANAGED MAINLY BY PHARMACOLOGICAL IMMUNOSUPPRESSION. MANY ORGANS RECIPIENTS’ QUALITY-OF-LIFE ARE COMPROMISED BECAUSE OF THE NON-SPECIFIC NATURE OF THE CURRENT THERAPIES. INDUCTION OF ALLOGRAFT IMMUNOLOGICAL TOLERANCE HAS BEEN THE PRIMARY GOAL OF NEW IMMUNOTHERAPIES AMONGST WHICH INFUSION OF REGULATORY T CELLS (TREGS) IS A PROMINENT STRATEGY BEING EVALUATED IN CLINICAL STUDIES. WHILE THE OUTCOMES OF SOME OF THE HUMAN TRIALS ARE PROMISING, THE COSTLY AND COMPLEX PROCESSES OF MANUFACTURING SEVERAL HUNDRED MILLION TREGS IN CLINICAL GRADE FACILITIES WILL LIMIT IN THE NEAR TERM THE NUMBER OF TRANSPLANT RECIPIENTS WHO WOULD BENEFIT FROM THE CELL-BASED THERAPY. IN THE CURRENT PROJECT WE SEEK TO ADVANCE AN ALTERNATIVE METHOD TO LEVERAGE TREG-MEDIATED TOLERANCE BY FORMULATING FIBROBLASTIC RETICULAR CELLS (FRCS) INTO INJECTABLE 3-DIMENSIONAL (3D) LYMPHOID NICHES. RODENT STUDIES HAVE SHOWN THAT FRCS EFFECTIVELY SUPPORT TREGS IN VIVO AND MEDIATE T CELL TOLERANCE. WHILE LYMPH NODE STROMAL CELLS CAN BE ISOLATED FROM PATIENTS IN ROUTINE BIOPSIES, ONLY A FEW STUDIES HAVE EVALUATED THE POTENTIAL OF FRCS AS THERAPEUTICS. INJECTION OF SINGLE-CELL FRCS RESULTS IN THEIR DISPERSION IN THE BODY AND DESTRUCTION OF THEIR NATIVE PHYSICAL AND BIOLOGICAL ATTRIBUTES. THE 3D FRCS FORMULATION WE HAVE DEVELOPED IS ENABLED BY A CROSS-LINKING POROUS BIOMATERIALS SCAFFOLD. THE INJECTABLE CLUSTERED FRCS (CLFRCS) WILL BE STUDIED IN TWO SPECIFIC AIMS. IN AIM 1 WE WILL OPTIMIZE THE PROTOTYPE TO GENERATE TREGS IN VITRO BY TUNING THE CROSS- LINKING DENSITY. IN AIM 2, THE PROTOTYPE AND THE TOP 2 PERFORMING OPTIMIZED CLFRCS FORMULATIONS WILL BE CHARACTERIZED IN HUMANIZED MOUSE MODELS TO TRACK THE MIGRATION OF FRCS AND THE CAPACITY OF THE CELL DEPOTS TO SUPPORT TREGS IN VIVO. OUR MPI TEAM IS UNIQUELY QUALIFIED TO ADVANCE THE RESEARCH GIVEN THE COMPLEMENTARY EXPERTISE IN BIOLOGICS DELIVERY AND MODELING T CELL HOMEOSTASIS IN HUMANIZED MOUSE MODELS. THE DATA GENERATED IN THIS WORK WILL PAVE THE WAY FOR TRANSLATIONAL STUDIES OF FRCS AS CELL THERAPIES AIMED AT TOLERANCE INDUCTION IN ALLOGRAFT TRANSPLANTATIONS.

THE IMPACT OF HEAT SHOCK PROTEIN 70 ON LEWY BODY DISORDERS

MOLECULAR BASIS OF BACTERIAL SPATIAL STRUCTURE FORMATION BY A POST-TRANSCRIPTIONAL REGULATOR

ORGANIC TRANSFORMATIONS VIA ACTIVATION OF MONOHALOGENATED SUBSTRATES IN COPPER CATALYZED ATOM TRANSFER RADICAL ADDITION

APPLICATION OF N-OXIDES FOR THE SYNTHESIS OF NITROGEN HETEROCYCLES - PROJECT SUMMARY: NITROGEN HETEROCYCLES ARE A UBIQUITOUS AND KEY STRUCTURAL MOTIF OF BIOACTIVE NATURAL PRODUCTS AND PHARMACEUTICALS WITH PROVEN EFFICACY TARGETING CANCER, PSYCHIATRIC DISORDERS, ANTIMICROBIALS, AND ANALGESICS. HOWEVER, THE SYNTHETIC STRATEGY OF INTRODUCING NEW NITROGEN HETEROCYCLES INTO A PHARMACEUTICAL FRAMEWORK IS NONTRIVIAL AND COSTLY, ESPECIALLY WHEN CONSIDERING COMPLEX THREE-DIMENSIONAL (3D) TARGETS. WE INTEND TO EXPAND UPON OUR RECENT BODY OF WORK THAT HAS IDENTIFIED N-OXIDE CHEMISTRY AS A PROMISING, INNOVATIVE, ADAPTABLE SOLUTION FOR THIS CONUNDRUM. TO CREATE NITROGEN HETEROCYCLES OF PHARMACOLOGICAL INTEREST, WE WILL USE N-OXIDES, EASILY PREPARED AND STABLE COMPOUNDS, AS PRECURSORS FOR [3+2] CYCLOADDITIONS. N-OXIDE COMPOUNDS WERE FIRST USED IN A LIMITED NUMBER OF CYCLOADDITION REACTIONS IN THE 1980S. HOWEVER, DESPITE SOLID AND LOGICAL REASONING AT THAT TIME, THE LACK OF MECHANISTIC UNDERSTANDING ON HOW THESE REACTIONS OCCURRED PREDICTED ELECTROPHILIC INTERMEDIATES THAT WOULD CAUSE SIDE REACTIONS, LOW YIELDS, AND POOR STEREOCHEMICAL CONTROL. CONSEQUENTLY, THE SYNTHETIC COMMUNITY UNDERVALUED THIS REACTION MANIFOLD AND AVOIDED SUCH AN APPROACH. HOWEVER, RE-EVALUATION OF THE ORIGINAL EXPERIMENTAL DATA WITH THE PERSPECTIVE OF HIGH-QUALITY DENSITY FUNCTIONAL THEORY, LED TO US UNCOVERING MECHANISTIC DETAILS DEFINING THE CRITICAL ROLE OF SOLVENT IN SUCH IONIC SYSTEMS, AND ERADICATED THE PREVIOUSLY CONCEIVED SYNTHETIC BARRIERS TO EFFICIENT USE. WE INTEND TO RESURRECT AND ESTABLISH THIS UNEXPLORED SYNTHETIC AVENUE FORMING NITROGEN HETEROCYCLES FROM SIMPLE PRECURSORS WITHOUT ONEROUS OVERHEAD AS A PRACTICAL AND SIGNIFICANT PROTOCOL IN MEDICINAL CHEMISTRY. BEYOND OUR PROPOSED WORK DELIVERING KEY ANALGESICS (AZA-BICYCLES), NOVEL ANTIMICROBIALS (IMIDAZOLINES), AND ENANTIO-ENRICHED SYSTEMS, THE IMPACT OF N- OXIDE CHEMISTRY HAS THE POTENTIAL FOR MANY NEW DIRECTIONS AND DISCOVERIES INCLUDING CYCLIC N-OXIDES, SILYL IMINES, AND N-CHIRAL COMPOUNDS. ALIGNED WITH NIH/R15 GOALS, THIS PROJECT HAS BEEN DESIGNED TO BE APPROACHABLE FOR STUDENTS OF ALL LEVELS OF EXPERIENCE IN EXPERIMENTAL AND/OR COMPUTATIONAL CHEMISTRY, ADAPTING THE EDUCATIONAL PHILOSOPHY OF UNIVERSAL DESIGN. INITIAL EXPERIMENTAL PROJECTS RANGE FROM PERFORMING AND OPTIMIZING ESTABLISHED REACTIONS UNDER SUPERVISION (BEGINNER) TO RUNNING NOVEL REACTIONS AND ANALYZING COMPLEX REACTION MIXTURES (ADVANCED/GRADUATE). LIKEWISE, ON THE COMPUTATIONAL SIDE STUDENTS CAN LEARN TO BUILD Z-MATRIXES AND IDENTIFY GROUND STATES FOR NEW ANALOGS (BEGINNER), PROGRESS TO FINDING TRANSITION STRUCTURES, PERFORMING ENERGY DECOMPOSITION ANALYSES AND DEVELOP CRITICAL ANALYSIS SKILLS (ADVANCED/GRADUATE). ULTIMATELY, OUR PLAN IS TO OPTIMIZE THIS N-OXIDE CHEMISTRY TO CREATE NITROGEN HETEROCYCLES AS THE CORE COMPONENT FOR ANALGESICS (AIM I), ANTIMICROBIALS (AIM II), AND STEREO-DEFINED 3D STRUCTURES (AIM III). THIS PROPOSAL OFFERS AN INNOVATIVE, ADAPTABLE STRATEGY FOR CREATING A WIDE RANGE OF SUCH COMPOUNDS THROUGH A SHARED REACTION PATHWAY THAT WILL EMPOWER THE PHARMACEUTICAL COMMUNITY TO EXPAND UPON ITS EFFORTS SIGNIFICANTLY IN THE DISCOVERY OF NOVEL DRUGS IN THE STRATEGIC AREAS OF ANTIMICROBIALS AND ANALGESICS.

USING PNAS TO ELUCIDATE THE ROLE OF G-QUADRUPLEX AND HAIRPIN STRUCTURES IN ALS/FTD THROUGH A COMBINED BIOPHYSICAL AND COMPUTATIONAL APPROACH

NEURAL STEM/PROGENITOR CELL FATE: PATHOLOGY AND PROTECTION DURING CNS INFECTIONS

FRAGILE X MENTAL RETARDATION PROTEIN TRANSLATION REGULATOR FUNCTION: INTERACTIONS

NOVEL SMALL MOLECULE INHIBITORS OF MEK5_ERK5 FOR THE TREATMENT OF BREAST CANCER

SPECIFYING NEUROPHYSIOLOGY AND PREDICTING REAL-WORLD IMPACT IN STUTTERING - PROJECT SUMMARY THE TERM ADVERSE IMPACT REFERS TO THE NEGATIVE PERSONAL REACTIONS, BROADER SPEECH- OR COMMUNICATION-RELATED CONSEQUENCES, AND OVERALL LIFE CHALLENGES THAT ADULTS WHO STUTTER MAY EXPERIENCE AS A RESULT OF THEIR SPEAKING DIFFICULTIES. THOUGH THE RISK OF BROADER LIFE IMPACT IS WIDELY ACKNOWLEDGED, PRIOR INVESTIGATIONS HAVE SOLELY EVALUATED THIS RISK VIA SURFACE SEVERITY, WHICH DOES NOT STRONGLY RELATE WITH NEGATIVE COGNITIVE-AFFECTIVE REACTIONS (NEGATIVE THOUGHTS AND FEELINGS). THIS LIMITS THE ABILITY OF CLINICIANS AND RESEARCHERS TO ACCURATELY IDENTIFY WHETHER SPECIFIC INDIVIDUALS ARE AT RISK FOR BROADER LIFE CONSEQUENCES ASSOCIATED WITH THEIR STUTTERING. SIMILARLY, MOST INVESTIGATIONS OF SPEECH NEUROPHYSIOLOGY IN PEOPLE WHO STUTTER RELY EXCLUSIVELY ON SURFACE SEVERITY TO GROUP AND INTERPRET DATA USING TASKS WITH LOW ECOLOGICAL VALIDITY (E.G., SPEAKING ALONE IN A SCANNER). THIS RAISES QUESTIONS ABOUT WHETHER THE FIELD’S CURRENT UNDERSTANDING OF SPEECH NEUROPHYSIOLOGY IS APPLICABLE TO REAL-WORLD ENVIRONMENTS WHERE PEOPLE WHO STUTTER SPEAK AND, AS A RESULT, EXPERIENCE NEGATIVE COGNITIVE-AFFECTIVE REACTIONS. THE PI’S PREVIOUS STUDIES SUGGEST THAT CONSIDERING SUB-GROUP DIFFERENCES IN COGNITIVE-AFFECTIVE REACTIONS (HOW SPEAKERS EXPERIENCE, MANAGE, AND COPE WITH STUTTERING) CAN PREDICT HOW SPEAKERS LET STUTTERING MANIFEST IN THEIR LIFE. PILOT DATA COLLECTED FOR THIS PROPOSAL SUGGEST THAT SUCH SUB-GROUP DIFFERENCES CAN ALSO PREDICT BROADER LIFE NEGATIVE OUTCOMES, SUCH AS SOCIAL ISOLATION. HOWEVER, IT IS UNKNOWN IF OTHER NEGATIVE LIFE OUTCOMES OFTEN ASSOCIATED WITH HIGHER RATES OF MORTALITY IN THE GENERAL POPULATION CAN BE PREDICTED FROM SUCH SUB-GROUP PERSPECTIVES. THEREFORE, FOR AIM 1, SUB-GROUP DIFFERENCES IN SPEAKER MANAGEMENT STRATEGIES WILL BE USED TO IDENTIFY RISK FACTORS FOR SOCIAL ISOLATION, CHARACTERISTICS OF DEPRESSION, AND CHARACTERISTICS OF ANXIETY. FOR AIM 2, WE WILL EXAMINE PATTERNS IN NEUROPHYSIOLOGY DURING SPEECH AND STUTTERING USING ECOLOGICALLY VALID SPEAKING SITUATIONS (SPEAKING IN FRONT OF A VIRTUAL AUDIENCE, INTERVIEWING FOR A JOB), WHILE SIMULTANEOUSLY ACCOUNTING FOR SUB-GROUP DIFFERENCES IN ONE NEGATIVE COGNITIVE-REACTION COMMON IN AWS, REPETITIVE NEGATIVE THINKING (RNT, I.E., RUMINATION). ENGAGING IN RNT TO HIGH DEGREES ACTIVATES RIGHT HEMISPHERE ATTENTION AREAS THAT OVERLAP WITH SPEECH MOTOR CONTROL, WHICH MAY IMPACT HOW WELL AWS COMPENSATE TO SPEECH MOTOR DEFICITS DURING SPEECH. OVERALL IMPACT: WE WILL RECONCEPTUALIZE STUTTERING SEVERITY BEYOND SURFACE FEATURES TO ACCOUNT FOR COGNITIVE- AFFECTIVE REACTIONS WHEN IDENTIFYING BROADER LIFE IMPACT AND EMPLOY THIS RECONCEPTUALIZATION IN STUDIES OF SPEECH NEUROPHYSIOLOGY IN ECOLOGICALLY VALID COMMUNICATION. DISCOVERIES FROM THIS RESEARCH WILL, FOR THE FIRST TIME, DIRECTLY CONNECT KNOWLEDGE OF THE UNDERLYING IMPAIRMENT (NEUROPHYSIOLOGICAL DIFFERENCES IN SPEECH AND LANGUAGE PRODUCTION) AND ADVERSE IMPACT (COGNITIVE-AFFECTIVE REACTIONS). FINDINGS WILL INCREASE THE UNDERSTANDING OF STUTTERING NEUROPHYSIOLOGY AND LEAD TO MORE EFFECTIVE AND TARGETED TREATMENT FOR PERSONALIZED INTERVENTIONS TO REDUCE HEALTH DISPARITIES AND INCREASE WELLBEING IN AWS.

REU SITE: INTEGRATION OF CHEMICAL THEORY, COMPUTATION AND EXPERIMENT AT DUQUESNE UNIVERSITY -THE RESEARCH EXPERIENCES FOR UNDERGRADUATES (REU) SITE AWARD TO DUQUESNE UNIVERSITY, LOCATED IN PITTSBURGH, PA, SUPPORTS THE TRAINING OF 10 STUDENTS FOR 10 WEEKS DURING THE SUMMERS OF 2023-2025. FUNDED BY THE DIVISION OF CHEMISTRY, THE DUQUESNE REU SITE CONTINUES TO IMPACT THE PROFESSIONAL CHEMISTRY CAREERS AND EDUCATION OF UNDERGRADUATES AND FACULTY FROM APPALACHIAN REGIONAL INSTITUTIONS WITH LIMITED RESEARCH INFRASTRUCTURE AND/OR FROM UNDERREPRESENTED POPULATIONS. TO MEET THIS CHALLENGE, DUQUESNE UNIVERSITY DELIVERS A QUALITY RESEARCH EXPERIENCE, WITH A FOCUS ON COMPUTATIONAL AND THEORETICAL CHEMISTRY, THAT MOTIVATES UNDERGRADUATES AND FACULTY TO ACHIEVE THEIR HIGHEST ACADEMIC PERFORMANCE AND BEST PREPARE THEM FOR SCIENTIFIC RESEARCH AND DISCOVERY. THE CORE IDEA IS TO ESTABLISH MEANINGFUL, YEAR-ROUND, AND LONG-TERM RESEARCH COLLABORATIONS DRIVEN BY THE NEED FOR ACADEMIC PRODUCTIVITY AND EXCELLENCE IN UNDERGRADUATE TRAINING. THE REU SITE SERVES NATIONAL INTEREST BY PROMOTING ADVANCES IN THE BASIC SCIENCES, TRAINING AND SUPPORT OF THE U.S. SCIENTIFIC WORKFORCE, AND ADVANCING PROSPERITY AND WELFARE. THIS PROJECT FOCUSES ON STRONG FINANCIAL AND INFRASTRUCTURE SUPPORT OF RESEARCH COLLABORATIONS THAT INVIGORATE PUI/HBC/LSAMP FACULTY, WHO IN TURN DIRECTLY IMPACT STUDENTS AND LEARNING ENVIRONMENTS AT THEIR HOME INSTITUTIONS. DUQUESNE HAS NSF-FUNDED RESOURCES, ESTABLISHED RESEARCH PROGRAMS, PROVEN RECORD IN STUDENT PLACEMENT, AND STRONG PARTNERSHIPS WITH LOCAL INDUSTRY. REU STUDENTS RECEIVE EXPLICIT TRAINING TO REINFORCE THE SCIENTIFIC METHOD, SCIENTIFIC WRITING AND SPEAKING, ETHICS, SAFETY, AND WORKSHOPS ON STATE-OF-THE-ART INSTRUMENTATION TO COMPLEMENT THEIR EXPERIMENTAL RESEARCH AND BUILD INVALUABLE SKILL SETS. EACH STUDENT HAS THE OPPORTUNITY TO PRESENT THEIR RESEARCH LOCALLY, REGIONALLY, AND NATIONALLY TO EXPAND THEIR PROFESSIONAL EXPOSURE AND NETWORKING TO MAKE MORE INFORMED CAREER DECISIONS AND BEST PREPARE FOR GRADUATE SCHOOL. THE PUI/HBC/LSAMP FACULTY ARE EMPOWERED THROUGH MEANINGFUL AND PRODUCTIVE ACADEMIC COLLABORATION TO ENHANCE THEIR PROFESSIONAL DEVELOPMENT. THE BROADER IMPACTS OF THIS WORK INCLUDE MEANINGFUL RESEARCH EXPERIENCES TO ATTRACT AND RETAIN THE NATION?S DIVERSE STUDENT TALENT POOL, WHICH HAS THE CONSEQUENCE OF ENHANCING AND DIVERSIFYING THE U.S. WORKFORCE BY ADDING EXPERTS IN THE FIELDS OF CHEMISTRY OR BIOCHEMISTRY. THIS AWARD REFLECTS NSF'S STATUTORY MISSION AND HAS BEEN DEEMED WORTHY OF SUPPORT THROUGH EVALUATION USING THE FOUNDATION'S INTELLECTUAL MERIT AND BROADER IMPACTS REVIEW CRITERIA.

REU SITE: INTEGRATION OF CHEMICAL THEORY, COMPUTATION AND EXPERIMENT AT DUQUESNE UNIVERSITY

NITRILE ANIONS: UUNMASKING FUNDAMENTAL REACTIVITY

NOVEL CYTOSKELETAL STABILIZERS AS POTENTIAL TREATMENTS FOR LIMBIC LEWY BODY DISORDERS

IMPACT OF N-ACETYL CYSTEINE ETHYL ESTER ON A-SYNUCLEIN PATHOLOGY IN THE OLFACTORY SYSTEM

MODULATION OF HERPES SIMPLEX VIRUS TYPE 1 GENOME STRUCTURE DURING LYTIC REPLICATION - HERPES SIMPLEX VIRUS TYPE 1 (HSV-1) IS A PREVALENT PATHOGEN THAT INFECTS THE MAJORITY OF THE HUMAN POPULATION. MUCH OF THE VIRUS LIFE CYCLE OCCURS IN THE NUCLEUS OF INFECTED CELLS, WHERE EVENTS THAT OCCUR ON THE VIRAL GENOME DETERMINE THE OUTCOME OF INFECTION. HOWEVER, HOW THE STRUCTURE OF THE VIRAL DNA CONTRIBUTES TO THE REGULATION OF KEY VIRAL PROCESSES IS NOT WELL UNDERSTOOD. VIRION HSV-1 DNA ENTERS INTO HOST CELLS CONTAINING SINGLE STRAND BREAKS AND SINGLE STRANDED GAPS. DURING VIRAL DNA REPLICATION, BRANCHED GENOME STRUCTURES FORM, LIKELY AS RECOMBINATION-MEDIATED REPLICATION INTERMEDIATES. WE PREVIOUSLY DEMONSTRATED THAT DISTINCT GROUPS OF CELLULAR DNA REPAIR PROTEINS ASSOCIATE WITH VIRAL GENOMES EARLY DURING INFECTION AND AFTER THE ONSET OF VIRAL DNA REPLICATION. HOW DNA DAMAGE IS NAVIGATED BY VIRAL DNA REPLICATION, TRANSCRIPTION, AND PACKAGING MACHINERY IS NOT UNDERSTOOD. FURTHERMORE, HOW THE GENOME-WIDE STRUCTURE OF THE HSV-1 GENOME IS MODIFIED DURING THE TEMPORAL PROGRESSION OF INFECTION HAS NOT BEEN DEFINED. A MAJOR ROADBLOCK TO PREVIOUSLY INVESTIGATE THESE QUESTIONS WAS THE INABILITY TO PROBE GENOME-WIDE DNA STRUCTURE. IN THIS EXPLORATORY PROPOSAL, WE DESCRIBE OUR PLAN TO DEVELOP APPROACHES TO DEFINE THE STRUCTURE OF THE HSV-1 GENOME THROUGHOUT PRODUCTIVE INFECTION. THE AIMS OUTLINED IN THIS PROPOSAL WILL ESTABLISH NEW APPROACHES TO MAP SINGLE AND DOUBLE STRAND BREAKS ON HSV-1 DNA AND INVESTIGATE VIRAL REPLICATION AND RECOMBINATION INTERMEDIATES IN VIVO. RESULTS WILL PROVIDE GREATER INSIGHT INTO MECHANISMS OF REGULATION OF HSV-1 TRANSCRIPTION, DNA REPLICATION, RECOMBINATION, AND REPAIR. FURTHERMORE, TOOLS GENERATED COULD BE ADAPTED TO PROBE HSV-1 GENOMES BEFORE AND AFTER REACTIVATION, VIRAL INFECTION IN CELLS DEFICIENT FOR SELECT CELLULAR DNA REPAIR AND DNA DAMAGE RESPONSE FACTORS, AND GENOMES OF OTHER DNA VIRUSES.

ENGINEERED EXTRACELLULAR VESICLES FOR THE DELIVERY OF MITOCHONDRIA AND THERAPEUTIC PROTEINS TO THE BBB - THE DAMAGE BORNE BY BRAIN ENDOTHELIAL CELLS (BECS) DISRUPTS THE STRUCTURE AND FUNCTION OF THE BLOOD-BRAIN BARRIER (BBB) AND CONTRIBUTES TO POOR PATIENT OUTCOMES POST-STROKE. IN THIS R01 PROPOSAL, WE WILL DETERMINE WHETHER ENGINEERED MICROVESICLES (MVS) CAN CO-DELIVER INNATE MV MITOCHONDRIA AND AN EXOGENOUS 27 KDA HEAT SHOCK PROTEIN (HSP27) TO PROTECT THE BBB VIA INCREASING BEC SURVIVAL AND BEC TIGHT JUNCTION INTEGRITY IN A MOUSE MODEL OF TRANSIENT CEREBRAL ISCHEMIA/REPERFUSION INJURY (STROKE). THIS ONE-TWO PUNCH STRATEGY USING ENGINEERED MVS CAN PROTECT THE POST ISCHEMIC-BBB METABOLIC FUNCTION AND STRUCTURAL INTEGRITY VIA EFFECTS OF THE INNATE MV MITOCHONDRIA AND THE EXOGENOUS HSP27 PROTEIN. MITOCHONDRIAL ATP REGULATES ACTIN DYNAMICS AND MAINTAINS PROPER ORGANIZATION OF THE ACTIN CYTOSKELETON. FURTHER, ATP DEPLETION-INDUCED CHANGES IN THE ACTIN EQUILIBRIUM CONTRIBUTES TO DYSREGULATION OF THE TIGHT JUNCTIONS, EVENTUALLY LEADING TO BBB DISRUPTION AND LONG-TERM NEUROLOGICAL DYSFUNCTION. ENDOTHELIAL BUT NOT NEURONAL EXPRESSION OF HSP27 IN A TRANSGENIC MOUSE MODEL SUPPRESSED I/R-INDUCED ABERRANT ACTIN POLYMERIZATION, STRESS FIBER FORMATION, AND JUNCTIONAL PROTEIN TRANSLOCATION—THAT OVERALL AMELIORATED NEUROLOGICAL DAMAGE FOR AS LONG AS ONE MONTH POST-STROKE. THIS SCIENTIFIC PREMISE STRONGLY SUPPORTS THE IMPORTANCE OF DECREASING DAMAGE TO THE BBB TO IMPROVE POST-STROKE OUTCOMES. MVS ARE A SUBTYPE OF EXTRACELLULAR VESICLES THAT NATURALLY INCORPORATE MITOCHONDRIA IN ADDITION TO ITS CONSTITUENT LIPIDS, NUCLEIC ACIDS AND PROTEINS. HSP27 IS A CATIONIC PROTEIN AND REQUIRES A CARRIER FOR ITS DELIVERY ACROSS ANIONIC CELL MEMBRANES. IN OUR FEASIBILITY STUDIES, WE HAVE DETECTED MITOCHONDRIA IN MVS AND ENGINEERED HSP27-MVS USING A SIMPLE FORMULATION PROCESS THAT ALLOWS TO RETAIN ITS FUNCTIONAL MITOCHONDRIAL LOAD. TO THIS END, WE HAVE DEMONSTRATED THAT (1) THE INNATE MITOCHONDRIA IN NAÏVE MVS CAN BE TRANSFERRED TO RECIPIENT PRIMARY HUMAN BECS AND MOUSE BRAIN CORTICAL AND HIPPOCAMPAL SLICES, (2) MVS BUT NOT THE SMALLER EXOSOMES INCREASE MITOCHONDRIAL FUNCTION IN OXYGEN-GLUCOSE DEPRIVED BECS (3) A SIMPLE FORMULATION PROCESS RESULTED IN >60% LOADING EFFICIENCY OF HSP27 INTO MVS AND (4) MICE INJECTED WITH NAÏVE MVS SHOWED NEARLY A 50% REDUCTION IN INFARCT VOLUME AND LOWER NEUROLOGICAL DEFICIT SCORES COMPARED TO VEHICLE-INJECTED MICE AFTER MIDDLE CEREBRAL ARTERY OCCLUSION (MCAO). WE HYPOTHESIZE THAT THE DELIVERY OF ENGINEERED HSP27-MVS, ALONG WITH THE INNATE MV MITOCHONDRIA WILL PROTECT THE METABOLIC FUNCTION AND STRUCTURAL INTEGRITY OF THE BECS LINING THE BBB—THAT IN COMBINATION WILL AMELIORATE THE BBB DISRUPTION-INDUCED CHANGES IN STROKE. WE WILL TEST THE PROPOSED HYPOTHESIS BY FIRST DETERMINING PROTECTIVE EFFECTS OF THE HSP27-MVS IN HYPOXIC BRAIN SLICES, OGD BECS AND IN ISOLATED BRAIN MICROVESSELS (AIMS 1 AND 2), CONDUCT A PHARMACOKINETICS STUDY TO DETERMINE THE OPTIMAL MV DOSE THAT SHOWS THE GREATEST BRAIN UPTAKE (AIM 2B) AND WE WILL DETERMINE THE THERAPEUTIC EFFICACY AND MECHANISTIC EFFECTS OF HSP27-MVS IN AGED MCAO MICE IN AIM 3. OVERALL, SUCCESSFUL COMPLETION OF THESE STUDIES WILL DEMONSTRATE IF BBB PROTECTION VIA INCREASING BEC ENERGETICS AND DECREASING BBB PERMEABILITY IMPROVES POST-STROKE OUTCOMES.

DEVELOPMENT OF A REGULATORY T CELL MIMETIC FOR TOLERANCE INDUCTION IN SKIN TRANSPLANTATION

DNA REPAIR AND ALPHA-SYNUCLEINOPATHY IN LEWY BODY DISORDERS

THE ROLE OF MEK5 IN MELATONIN-INDUCED OSTEOBLAST AND OSTEOCLAST DIFFERENTIATION

PHOTOPROBES FOR IDENTIFYING POTENTIAL ANTI-DEPRESSANT AND ANTI-ANXIETY MEDICATION

SYNTHESIS AND PROPERTIES OF MAGNETIC CERAMIC NANOPARTICLES

DUQUESNE UNIVERSITY CYBERSECURITY INITIATIVE II

NON-VIRAL GENETIC MODIFICATION OF ANTIGEN-PRESENTING CELLS IN ALLOGRAFTS

FY09 ONE-TIME GRANT COMPETITION - COMPETITION B - PROFESSIONAL, CULTURAL, YOUTH PROGRAMS

FUNCTIONAL STUDIES OF THE FRAGILE X MENTAL RETARDATION PROTEIN: SWITCHING FROM RE

MRI: ACQUISTION OF A CONFOCAL MICROSCOPE FOR RESEARCH AND TEACHING

NON-TROPANE IRREVERSIBLE DOPAMINE TRANSPORTER LIGANDS

METALATED NITRILES: UNMASKING FUNDAMENTAL REACTIVITY

THERANOSTIC PAIN NANOMEDICINES: IMAGING INFLAMMATION, REDUCING PAIN AND NEED FOR OPIOIDS

A BIOMATERIAL APPROACH TO ATTENUATE REJECTION OF SKIN ALLOGRAFTS

MRI: ACQUISITION OF A SCANNING ELECTRON MICROSCOPE FOR IMAGING AND ELEMENTAL ANALYSIS IN RESEARCH AT DUQUESNE UNIVERSITY

NURSE FACULTY LOAN PROGRAM

REU SITE: DISCOVERY BY COMPUTATION, THEORY AND EXPERIMENT

CAREER & TECHNICAL EDUCATION

INTEGRATED COMPUTATIONAL AND EXPERIMENTAL REU SITE

CATALYST: AN INSTITUTIONAL SELF-ASSESSMENT OF SERVICE EQUITY AND IMPACT OF SERVICE ON UNDERREPRESENTED FACULTY IN STEM AT DUQUESNE UNIVERSITY -DUQUESNE UNIVERSITY WILL UNDERTAKE AN INSTITUTIONAL SELF-ASSESSMENT TO IDENTIFY POTENTIAL ORGANIZATIONAL INEQUITIES IN CULTURE AND POLICY THAT RESULT IN DIFFERENTIAL PROFESSIONAL OUTCOMES FOR SOME STEM FACULTY. THE ADVANCE CATALYST PROJECT WILL RESULT IN A FIVE-YEAR STEM FACULTY EQUITY PLAN TAILORED TO THE DUQUESNE UNIVERSITY CONTEXT AND INSTITUTIONAL DATA THAT WILL GUIDE INSTITUTIONAL ACTIONS TO ADDRESS ANY ISSUES IDENTIFIED DURING THE GRANT. THIS PROJECT WILL EXAMINE HOW CULTURE, POLICY, AND OTHER FACTORS INTERACT ACROSS LEVELS OF AN INSTITUTION AND AFFECT DIFFERENT FACULTY IN STEM. THE INSTITUTIONAL SELF-ASSESSMENT AND FIVE-YEAR STRATEGIC PLAN WILL SET A FOUNDATION TO IMPROVE EQUITY FOR STEM FACULTY AT THE INSTITUTION. THIS WORK WILL BENEFIT STEM DISCIPLINES AS WELL AS NON-STEM DISCIPLINES DUE TO THE INTERCONNECTED NATURE OF INSTITUTIONAL POLICY. RESULTS OF THE CATALYST PROJECT WILL BE REGULARLY COMMUNICATED WITH THE DUQUESNE UNIVERSITY COMMUNITY. THE PROJECT IS EXPECTED TO ADD TO OUR UNDERSTANDING OF STEM FACULTY EQUITY ISSUES AT PRIVATE CATHOLIC INSTITUTIONS WITH SERVICE-FOCUSED MISSIONS. THE NSF ADVANCE PROGRAM IS DESIGNED TO FOSTER GENDER EQUITY THROUGH A FOCUS ON THE IDENTIFICATION AND ELIMINATION OF ORGANIZATIONAL BARRIERS THAT IMPEDE THE FULL PARTICIPATION AND ADVANCEMENT OF DIVERSE FACULTY IN ACADEMIC INSTITUTIONS. ORGANIZATIONAL BARRIERS THAT INHIBIT EQUITY MAY EXIST IN POLICIES, PROCESSES, PRACTICES, AND THE ORGANIZATIONAL CULTURE AND CLIMATE. ADVANCE CATALYST AWARDS PROVIDE SUPPORT FOR INSTITUTIONAL EQUITY ASSESSMENTS AND THE DEVELOPMENT OF FIVE-YEAR FACULTY EQUITY STRATEGIC PLANS AT ACADEMIC, NON-PROFIT INSTITUTIONS OF HIGHER EDUCATION. THIS AWARD REFLECTS NSF'S STATUTORY MISSION AND HAS BEEN DEEMED WORTHY OF SUPPORT THROUGH EVALUATION USING THE FOUNDATION'S INTELLECTUAL MERIT AND BROADER IMPACTS REVIEW CRITERIA.- SUBAWARDS ARE NOT PLANNED FOR THIS AWARD.

REU SITE: INTERDISCIPLINARY BIOLOGICAL SCIENCES RESEARCH AND COMMUNITY ENGAGED LEARNING EXPERIENCES FOR UNDERGRADUATES

MOLECULAR EVOLUTION OF HOMINOID PROTEINS

A NOVEL GRAFT IMPLANTED MACROPHAGE-ENZYME RESPONSIVE IMMUNOSUPPRESSIVE THERAPY (MERIT) TO PREVENT CHRONIC REJECTION IN VASCULARIZED COMPOSITE ALLOTRANSPLANTATION. NEW AWARD.

FIE EARMARK GRANT AWARDS

CHEMISTRY REU LEADERSHIP GROUP

CHROMOSOME SEGREGATION IN A FILAMENTOUS BACTERIUM

ENHANCING EXPERIMENTAL RIGOR THROUGH EDUCATION IN EVIDENCE SYNTHESIS - PROJECT SUMMARY/ABSTRACT MORE RESEARCH IS BEING PUBLISHED NOW THAN ANY OTHER TIME IN HISTORY AND THAT RESEARCH IS ACCESSIBLE WORLDWIDE. DUE TO THE RAPID PROLIFERATION OF RESEARCH, IT CAN BE DIFFICULT IF NOT IMPOSSIBLE FOR AN INDIVIDUAL TO STAY ABREAST OF IMPORTANT FINDINGS WHICH CAN IMPACT RESEARCH AND EVIDENCE-BASED PRACTICE. YET, HAVING A COMPREHENSIVE UNDERSTANDING OF THE LITERATURE IS FOUNDATIONAL TO ADVANCING KNOWLEDGE. THIS ALLOWS A RESEARCHER TO IDENTIFY EXISTING GAPS IN KNOWLEDGE SO THAT THEY CAN DESIGN NEW RESEARCH TO ADVANCE THE AREA FORWARD. ONE WAY TO ACHIEVE THIS IS THROUGH A RIGOROUS EVIDENCE SYNTHESIS, OR A SYSTEMATIC APPROACH TO GATHERING AND ANALYZING RESULTS FROM MULTIPLE SOURCES. IN PRACTICE, THE USE OF EVIDENCE SYNTHESES REQUIRES IMPROVEMENT, AS THEY ARE OFTEN POORLY CONDUCTED AND REPORTED, WHICH HAS SERIOUS DOWNSTREAM IMPACTS ON PUBLIC HEALTH. WHILE THERE ARE AMPLE RESOURCES CURRENTLY AVAILABLE TO RESEARCHERS ON THE TOPIC, THEY ARE UNDERUTILIZED AND MAY NOT BE FULLY ACCESSIBLE TO ALL INDIVIDUALS WHO MAY BENEFIT FROM THEM. THE NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE (NINDS) SEEKS TO IMPROVE FUNDAMENTAL KNOWLEDGE THROUGH TIMELY DISSEMINATION OF SCIENTIFIC DISCOVERIES IN THE AREA OF NEUROLOGICAL DISEASE. THIS MISSION, ACROSS THE TRANSLATIONAL SPECTRUM, IS FULLY SUPPORTED BY ENHANCING SKILLS IN EVIDENCE SYNTHESIS, WHICH CAN PREVENT WASTE IN RESEARCH INVESTMENT. AS KNOWLEDGE OF THE BRAIN AND NERVOUS SYSTEM ADVANCES RAPIDLY, SCIENTISTS IN THIS AREA HAVE TO BE HIGHLY REFLEXIVE TO CHANGING CURRENT KNOWLEDGE TO ENSURE THAT THEIR WORK IS RELEVANT. TRAINING IN THE SKILLS OF EVIDENCE SYNTHESIS ENABLES THIS. ACCORDINGLY, THE AIM OF THIS PROPOSAL IS TO DEVELOP, EVALUATE, AND DISSEMINATE A SERIES OF EDUCATIONAL MODULES ON RIGOROUS APPROACHES TO SCIENCE FOCUSED ON EVIDENCE SYNTHESIS. THE PROPOSED MODULES WILL COVER (1) AN INTRODUCTION TO EVIDENCE SYNTHESIS, (2) DEVELOPING A RESEARCH QUESTION AND PROPOSAL, (3) DESIGNING LITERATURE SEARCHES, (4) CONDUCTING AN EVIDENCE SYNTHESIS, (5) ANALYZING DATA FROM AN EVIDENCE SYNTHESIS, AND (6) REPORTING RESULTS FROM AN EVIDENCE SYNTHESIS. THE MODULES WILL BE DESIGNED TO BE UTILIZED BY DIFFERENT LEVELS OF LEARNERS (INTRODUCTORY, INTERMEDIATE, AND ADVANCED) AND APPLY ACROSS THE TRANSLATIONAL SPECTRUM (BASIC SCIENCE, CLINICAL SCIENCE, AND PUBLIC HEALTH). MODULE DEVELOPMENT, EVALUATION, AND DISSEMINATION WILL OCCUR WITH AN ITERATIVE PROCESS OF REVIEW AND FEEDBACK ACROSS MULTIPLE STAKEHOLDERS (EXPERTS AND LAY PERSONS ALIKE) TO CREATE A USEFUL AND COMPREHENSIVE FINAL PRODUCT. THE OPPORTUNITY TO IMPROVE THE USE OF EVIDENCE SYNTHESIS TECHNIQUES THROUGH A PLATFORM THAT IS ACCESSIBLE TO ALL INTERESTED SCIENTISTS HAS SIGNIFICANT POTENTIAL TO ENHANCE SCIENTIFIC RIGOR, AND ULTIMATELY, IMPROVE PUBLIC HEALTH.

MRI: SUSCHEM: ACQUISITION OF A HYBRID DISTRIBUTED COMPUTER SYSTEM TO ENHANCE INTEGRATION OF CHEMICAL THEORY, COMPUTATION, AND EXPERIMENTAL RESEARCH AT DUQUESNE UNIVERSITY

MRI: ACQUISITION OF LARGE SHARED MEMORY SUPERCOMPUTER AT DUQUESNE UNIVERSITY

INTEGRATED COMPUTATIONAL AND EXPERIMENTAL REU/DOD SITE

A PARTNERSHIP IN NEUROSCIENCE EDUCATION

LEAPS-MPS: EXAMINATION OF KNOT INVARIANTS VIA COMPUTATIONAL METHODS -THIS PROJECT INVESTIGATES KNOT THEORY; A FIELD OF MATHEMATICS CONCERNED WITH UNDERSTANDING HOW LOOPS (LIKE KNOTS IN A STRING) CAN BE EMBEDDED AND MANIPULATED IN THREE-DIMENSIONAL SPACE. KNOT THEORY IS PART OF THE BROADER AREA OF TOPOLOGY, WHICH STUDIES THE PROPERTIES OF SHAPES THAT REMAIN UNCHANGED WHEN STRETCHED OR BENT. WHILE ABSTRACT IN NATURE, KNOT THEORY PLAYS A ROLE IN MANY SCIENTIFIC DOMAINS: MOLECULAR BIOLOGY (WHERE IT HELPS EXPLAIN DNA FOLDING), PHYSICS (IN THE STUDY OF QUANTUM ENTANGLEMENT), AND COMPUTER SCIENCE (IN DATA ANALYSIS). THE RESEARCH WILL FOCUS ON MATHEMATICAL OBJECTS CALLED INVARIANTS: QUANTITIES OR PROPERTIES THAT REMAIN UNCHANGED WHEN A KNOT IS DEFORMED IN SPECIFIC WAYS. THESE ARE CRUCIAL TOOLS FOR DISTINGUISHING BETWEEN DIFFERENT TYPES OF KNOTS AND UNDERSTANDING THEIR STRUCTURE. THE PROJECT AIMS TO UNCOVER NEW PATTERNS, PROPOSE NOVEL TOOLS FOR IDENTIFICATION FOR CERTAIN FAMILIES OF KNOTS, AND PUSH THE BOUNDARIES OF WHAT IS COMPUTATIONALLY ACCESSIBLE IN TOPOLOGY. TO ADVANCE THIS WORK, THE PROJECT INCORPORATES MACHINE LEARNING, A FORM OF ARTIFICIAL INTELLIGENCE WHERE COMPUTERS DETECT PATTERNS IN DATA, AND PREDICTIVE MODELING, WHICH USES DATA TO MAKE STATISTICALLY INFORMED GUESSES ABOUT UNKNOWN OR COMPLEX SYSTEMS. IN ADDITION, THE PI WILL INVOLVE UNDERGRADUATE STUDENTS IN ACTIVE RESEARCH AND DEPARTMENTAL PROGRAMS, CREATE COMPUTATIONAL PACKAGES TO SUPPORT FURTHER EXPLORATION, AND ENGAGE WITH K?12 COMMUNITIES THROUGH OUTREACH PROGRAMS. THIS WORK CONSISTS OF SEVERAL INTERRELATED RESEARCH TOPICS, EACH ADDRESSING CENTRAL QUESTIONS IN KNOT THEORY BY BRIDGING CLASSICAL AND MODERN HEEGAARD FLOER-THEORETIC PERSPECTIVES WITH USE OF COMPUTATIONAL METHODS. WITH THE HELP OF MACHINE LEARNING, THE PI WILL UNCOVER NEW RELATIONSHIPS BETWEEN THE ALEXANDER POLYNOMIAL AND VARIOUS FLOER-THEORETIC INVARIANTS, EXAMINING HOW L-SPACE KNOTS BEHAVE IN THE KNOT CONCORDANCE GROUP. THE PI ALSO AIMS TO DEVELOP A NEW INVARIANT WHICH IS EXPECTED TO GENERALIZE, IN SOME SENSE, BOTH THE UPSILON FUNCTION AND THE UPSILON TORSION FUNCTION. USING RELATED TECHNIQUES COMBINED WITH CLASSICAL STUDY OF COVERS OF KNOTS, THE PI AND HER COLLABORATOR WILL DEVELOP PRIME KNOT DETECTION RESULTS. IN WORK WITH HER COLLABORATORS, THE EXPLORATION OF NULL-HOMOLOGOUS TWISTING WILL PRODUCE GENERALIZATIONS OF KNOWN RESULTS FOR THE UNKNOTTING NUMBER. THIS AWARD REFLECTS NSF'S STATUTORY MISSION AND HAS BEEN DEEMED WORTHY OF SUPPORT THROUGH EVALUATION USING THE FOUNDATION'S INTELLECTUAL MERIT AND BROADER IMPACTS REVIEW CRITERIA.- SUBAWARDS ARE NOT PLANNED FOR THIS AWARD.

SYSTEMIC TRAVEL OF DAMAGED DNA IN PHOTOSENSITIVE AUTOIMMUNE DISORDERS - THE GENOME IN HUMAN SKIN IS ROUTINELY DAMAGED BY ULTRAVIOLET (UV) RADIATION AND OTHER ENVIRONMENTAL GENOTOXINS THAT ARE KNOWN TO INDUCE SYSTEMIC INFLAMMATION. MY RECENT WORK DEMONSTRATES THAT KERATINOCYTES EXPOSED TO UVB RADIATION RELEASE 100-200NM PARTICLES CONTAINING DNA WITH CYCLOBUTANE PYRIMIDINE DIMERS (CPDS), OR ADDUCT-CONTAINING DNA (ACDNA), THAT ARE CAPABLE OF BEING TAKEN UP BY BYSTANDER CELLS. MY PRELIMINARY EVIDENCE INDICATES CPD TRANSPORT TO LYMPH NODES AND KIDNEY IN MICE, AND OTHERS HAVE MEASURED CPD EXCRETION IN HUMAN URINE. HOWEVER, THE ROLE OF EXTRACELLULAR ENVIRONMENTAL GENOTOXIN-DAMAGED DNA IN SYSTEMIC INFLAMMATORY RESPONSES HAS NOT PREVIOUSLY BEEN EXPLORED. MANY PATIENTS WITH AUTOINFLAMMATORY DISORDERS, SUCH AS LUPUS, HAVE PHOTOSENSITIVITY. MOREOVER, NEARLY TWO-THIRDS PRESENT WITH REDUCED ACTIVITIES OF NUCLEASES THAT DEGRADE IMMUNOGENIC CIRCULATING EXTRACELLULAR DNA. THE LACK OF UNDERSTANDING ABOUT THE ROLE OF EXTRACELLULAR ACDNA IN AUTOIMMUNE DISORDERS PRESENTS A MAJOR GAP IN THE FIELD. THUS, THE OBJECTIVE OF THIS APPLICATION IS TO TEST MY HYPOTHESIS THAT DEFICIENCIES IN SERUM NUCLEASE ACTIVITY AND THE PRESENCE OF UV PHOTOPRODUCTS COMPOUND SYSTEMIC INFLAMMATORY RESPONSES IN PATIENTS WITH PHOTOSENSITIVE AUTOIMMUNE DISORDERS. FIRST, AIM 1 (K99) SEEKS TO DEMONSTRATE CPD CONTENT IN URINE EVS AND CORRELATE ACDNA CONTENT WITH LUPUS DISEASE SEVERITY INDICATORS AND SERUM NUCLEASE ACTIVITY. TO FURTHER MAP SYSTEMIC CIRCULATION AND IMPACT OF ACDNA, AIM 2 (K99/R00) WILL MEASURE ACDNA TRANSFER TO ORGANS AND DAMAGE-DEPENDENT RESPONSES IN MOUSE MODELS OF LUPUS WITH NUCLEASE DEFICIENCIES. LASTLY, AIM 3 (R00) WILL DEFINE MECHANISMS OF RELEASE AND RESPONSE OF ACDNA IN EVS IN CONTEXT OF COMMON AUTOIMMUNE NUCLEASE DEFICIENCIES. THESE FINDINGS WILL HAVE BROAD APPLICABILITY TO THE NIEHS BECAUSE OUR MODEL OF UVB-DAMAGED DNA TRANSFER IS EXPECTED TO EXTEND TO OTHER ACDNA-INDUCING ENVIRONMENTAL GENOTOXINS. THUS, MY RESEARCH FINDINGS MAY IMPROVE TREATMENTS FOR PHOTOSENSITIVE AUTOIMMUNE DISORDERS AND PROVIDE NEW WAYS OF QUANTIFYING ENVIRONMENTAL GENOTOXIN EXPOSURE. THIS AWARD WILL ASSIST THE ESTABLISHMENT OF A NEW LAB IN THE DEPARTMENT OF CHEMISTRY AND BIOCHEMISTRY AT DUQUESNE UNIVERSITY. I WILL LEVERAGE MY EXPERTISE IN CHEMISTRY, BIOCHEMISTRY, AND MOLECULAR BIOLOGY TO ESTABLISH A LAB STUDYING CELL-FREE DAMAGED DNA. FURTHERMORE, SYSTEMS ESTABLISHED IN THE K-STAGE WILL PROVIDE A MENTORSHIP FRAMEWORK FOR CONTINUED GUIDANCE BY EXPERTS IN THE FIELD (DRS. KEMP, TRAVERS, CRAWFORD, BROWN, MAHONEY). RECEIPT OF THIS AWARD WILL ENHANCE MY TRANSITION TO AN INDEPENDENT RESEARCH FACULTY AND WILL FACILITATE TRANSLATIONAL RESEARCH ON THE IMPACT OF CIRCULATING DAMAGED DNA.

KINASE SIGNALING IN AGING DOPAMINE NEURONS

SATC: CORE: SMALL: COLLABORATIVE: DEFENDING AGAINST AUTHORSHIP ATTRIBUTION ATTACKS

HIGH EFFICIENCY SCREENING OF BIOACTIVE LIPIDS

AF:SMALL:RUI:NEW DIRECTIONS IN FOURIER ANALYSIS, NOISE SENSITIVITY, AND LEARNING THEORY

STUDIES OF THE PROTON STRUCTURE WITH ELECTRON BEAMS -HALF A CENTURY OF EXPERIMENTAL INVESTIGATIONS INTO THE PROTON'S INTERNAL STRUCTURE HAVE PROVIDED REMARKABLE INSIGHT INTO THE DYNAMICS OF THE QUARKS AND GLUONS MAKING UP THE PARTICLE. HOWEVER, MANY OUTSTANDING QUESTIONS REMAIN. EVEN THE MOST FUNDAMENTAL ASPECT, THE ORIGIN OF THE MASS OF NUCLEI, IS UNCERTAIN. TO DATE, THE MOST VISIBLE MASS OF THE UNIVERSE, AS WELL AS A COMPLETE DESCRIPTION OF HOW QUARKS ARE CONFINED INTO COMPOSITE PARTICLES REMAIN OUTSIDE OUR CURRENT UNDERSTANDING. THE PI AND HER DUQUESNE UNDERGRADUATE STUDENTS WILL INVESTIGATE THE ORIGIN OF THE SPIN OF THE PROTON THROUGH ITS FUNDAMENTAL CONSTITUENTS, USING ELECTRON BEAMS AT THE THOMAS JEFFERSON NATIONAL ACCELERATOR FACILITY. THIS AWARD SUPPORTS THE PI AND DUQUESNE UNDERGRADUATE STUDENTS IN RESEARCH AIMING TO STUDY THE STRUCTURE OF THE PROTON THROUGH ITS PARTONIC DISTRIBUTIONS USING POLARIZED ELECTRON SCATTERING IN THE DEEP INELASTIC SCATTERING REGIME IN HALL B AT JEFFERSON LAB. THESE MEASUREMENTS WILL HELP UNDERSTAND THE ORIGIN OF SINGLE HADRON FORMATION INSIDE THE PROTON. COMBINED WITH ADDITIONAL MEASUREMENTS ON DEUTERIUM TARGETS, THE PI WILL BE ABLE TO PROBE THE STRANGENESS CONTRIBUTION TO THE STRUCTURE OF THE NUCLEON THROUGH ITS PARTONIC DISTRIBUTION USING CHARGED KAON AND PION DETECTION. THE DUQUESNE GROUP WILL PARTICIPATE IN MONITORING AND MAINTAINING THE SOFTWARE FOR TWO HYBRID RING IMAGING CHERENKOV DETECTORS THAT ARE IMPORTANT FOR PARTICLE IDENTIFICATION. SOFTWARE DEVELOPMENT AND PHYSICS DATA ANALYSIS WILL BE PERFORMED AT DUQUESNE, WHILE ELECTRONICS TESTING AND OTHER HARDWARE PROJECTS WILL BE PERFORMED AT JEFFERSON LAB. THIS PROJECT WILL PROVIDE UNDERGRADUATE STUDENTS WITH OPPORTUNITIES TO FURTHER THEIR TRAINING AND EDUCATION OUTSIDE OF THE CLASSROOM. THIS INCLUDES GAINING EXPERIENCE IN THE DESIGN, ASSEMBLY, AND TESTING OF MODERN PARTICLE PHYSICS DETECTORS, HIGH TECH FAST ELECTRONICS, AND SCIENTIFIC DATA ANALYSIS. THIS AWARD REFLECTS NSF'S STATUTORY MISSION AND HAS BEEN DEEMED WORTHY OF SUPPORT THROUGH EVALUATION USING THE FOUNDATION'S INTELLECTUAL MERIT AND BROADER IMPACTS REVIEW CRITERIA.

TAS::970130::TAS 'A TARGETED, LOCAL, NON-OPIOID THERAPEUTIC STRATEGY FOR MITIGATION, MODULATION AND MGMT OF TRAUMA INDUCED NEURO PAIN'

SUPPRESSION OF TADPOLE LIMBS: A MODEL FOR ORGAN SIZE REGULATION

RESEARCH EXPERIENCES FOR UNDERGRADUATES: INTEGRATED COMPUTATIONAL AND EXPERIMENTAL REU SITE AT DUQUESNE UNIVERSITY

PARTON DISTRIBUTIONS IN THE NUCLEON

PREVENTION OF BIOFILM GROWTH ON ORTHOPEDIC IMPLANT MATERIALS THROUGH CHEMICAL SUR

RUI: STUDIES OF PARTON DISTRIBUTIONS USING KAONS AT JEFFERSON LAB

SYNTHESIS AND TESTING OF RIGID CDK5 INHIBITORS

RAPID: CONSERVED REGIONS OF THE SARS-COV-2 VIRUS (COVID-19) RNA-RNA INTERACTIONS THAT MEDIATE GENOME DIMERIZATION AND/OR PROGRESSION THROUGH THE VIRAL LIFE CYCLE

ERI: A NOVEL MULTIPHYSICS FRAMEWORK FOR FLUID CIRCULATION AND OXYGEN TRANSPORT IN VOCAL FOLDS

ADVANCED EDUCATION NURSING TRAINEESHIPS

RUI: NEW VARIATIONAL MODELS FOR DENOISING, DECOMPOSITION, AND DEBLURRING

RUI: NEW APPLICATIONS OF CURVATURE IN IMAGE PROCESSING

CONFERENCE: CONFERENCE: SUPPORT FOR CONFERENCE EXPERIENCE FOR UNDERGRADUATE STUDENTS AT THE DNP MEETING -THE DIVISION OF NUCLEAR PHYSICS ANNUAL MEETING BRINGS TOGETHER THE COUNTRY'S NUCLEAR PHYSICISTS TO SHARE THE NEWEST SCIENTIFIC DISCOVERIES AND ADVANCES IN PARTICLE DETECTORS AND TECHNOLOGIES. HUNDREDS OF UNDERGRADUATE AND GRADUATE STUDENTS ATTEND THIS MEETING AND ARE CONSIDERING A CAREER IN NUCLEAR SCIENCE OR RELATED FIELDS. THESE STUDENTS WILL CREATE THE FUTURE WORKFORCE AND CONTRIBUTE TO A VARIETY OF FIELDS FROM BASIC SCIENCE TO NUCLEAR MEDICINE, DEFENSE, AND NATIONAL SECURITY, AND INDUSTRY FIELDS THAT WILL MAKE USE OF THEIR KNOWLEDGE OF NUCLEAR PHYSICS. THIS AWARD WILL AID IN THE RETENTION OF BOTH GROUPS OF STUDENTS BY PARTIALLY SUPPORTING THE UNDERGRADUATE STUDENTS TO ATTEND THE CONFERENCE EXPERIENCE FOR UNDERGRADUATES (CEU) AND A NEAR-PEER MENTORING NETWORK, FOR TWO YEARS. GRADUATE STUDENTS AND POSTDOCTORAL RESEARCHERS (NEAR-PEERS) WILL BE RECRUITED TO MENTOR THE UNDERGRADUATE STUDENTS IN ATTENDANCE. THE MENTORS WILL PARTICIPATE IN AN 8-HOUR MENTORING WORKSHOP AT THE BEGINNING OF THE CONFERENCE AND THEN APPLY THESE SKILLS DURING THE CONFERENCE WITH THEIR ASSIGNED UNDERGRADUATE MENTEES. THE 2025 AND 2026 DNP MEETINGS WILL TAKE PLACE IN CHICAGO AND PHILADELPHIA, RESPECTIVELY. THE CEU PROGRAM IS A NATURAL VENUE FOR STUDENTS WHO HAVE HAD AN UNDERGRADUATE NUCLEAR PHYSICS RESEARCH EXPERIENCE TO PRESENT THE RESULTS OF THEIR RESEARCH AND INTERACT WITH OTHER STUDENTS, GRADUATE STUDENTS, AND POSTDOCS, AS WELL AS FACULTY AND SENIOR RESEARCHERS IN THE FIELD. THE CEU PROGRAM HAS BEEN VERY SUCCESSFUL IN FOSTERING THESE INTERACTIONS, WHICH HELPS STUDENTS GET AN INTRODUCTION AND EXPOSURE TO RESEARCH ACROSS NUCLEAR PHYSICS, AND TO ENABLE SENIOR RESEARCHERS TO GET TO KNOW SOME OF THEIR JUNIOR COLLEAGUES. THE GOAL OF THIS MENTORING PROGRAM IS TO ENCOURAGE STUDENTS TO SEE THEMSELVES AS SCIENTISTS AND CONTINUE INTO NUCLEAR SCIENCE CAREERS AS EMPHASIZED IN THE 2023 LONG RANGE PLAN FOR NUCLEAR SCIENCE. THIS AWARD REFLECTS NSF'S STATUTORY MISSION AND HAS BEEN DEEMED WORTHY OF SUPPORT THROUGH EVALUATION USING THE FOUNDATION'S INTELLECTUAL MERIT AND BROADER IMPACTS REVIEW CRITERIA.- SUBAWARDS ARE PLANNED FOR THIS AWARD.

GRADUATE RESEARCH FELLOWSHIP PROGRAM (GRFP)

A MACHINE-AIDED BACK-OF-THE-BOOK INDEXING SYSTEM

NEUROCOGNITIVE BASIS OF LANGUAGE PROCESSING IN AUTISM

CO-DEVELOPING A CURRICULUM COHERENCE TOOLKIT WITH TEACHERS

COLLABORATIVE RESEARCH: A PHYLOGENY OF PLACENTAL MAMMALS BASED ON PALEOCENE TAXA: DETERMINING THE IMPACT OF THE K-PG EXTINCTION ON MAMMALIAN EVOLUTIONARY HISTORY

DEVELOPMENT OF AGE-APPROPRIATE FAST DISINTEGRATING PEDIATRIC GRANULES AND TABLETS

LEARNING GEOMETRY FOR INVERSE PROBLEMS IN IMAGING

PARADISE LOST AND THE CONTEMPORARY READER

ARRA - NURSE FACULTY LOAN PROGRAM

GENERATING SYSTEMIC ANTITUMOR IMMUNITY IN RENAL CELL CARCINOMA BY INTRATUMORAL INJECTION OF MULTIPLEXED ANTI-PD-1 ANTIBODY AND ADENOSINE DEAMINASE

CONTINUED INVESTIGATIONS OF ALTERNATIVE ANAEROBIC BIOGEOCHEMICAL REDOX CYCLES IN VOLCANIC HYPERSALINE ENVIRONMENTS: EARTH MARS AND EUROPA. A RE-RE

INVESTIGATION OF CELL-TYPE SPECIFIC CONTRIBUTIONS TO BLADDER PAIN MODULATION IN THE CENTRAL AMYGDALA

EARMARKS

DIRECTED GRANTS

CONTINUED INVESTIGATIONS OF "ALTERNATIVE" ANAEROBIC BIOGWOCHEMICAL REDOX CYCLES OF VOLCANIC HYPERSA

LOW INCOME TAXPAYER CLINIC

LOW INCOME TAXPAYER CLINIC

ARRA - NURSE FACULTY LOAN PROGRAM

CRI: CRD: COLLABORATIVE RESEARCH: COMMUNITY RESOURCES FOR AUTHORSHIP ATTRIBUTION RESEARCH

EFFECTS OF CENTRAL AMYGDALA LATERALIZATION ON DESCENDING CONTROL OF BLADDER PAIN

A NOVEL MECHANISM OF ACTION FOR N-ACETYL CYSTEINE

THEORETICAL QUESTIONS OF ANALYSIS AND ASTROPHYSICS IN THE EINSTEIN EQUATIONS

TAKING HUMANITIES TO THE HILL: UNIVERSITY COMMUNITY WRITING CENTER STORYTELLING INITIATIVES [THE COMMUNITY WRITING CENTER (CWC) EXTENDS THE SERVICES OF DUQUESNE UNIVERSITY?S ON-CAMPUS WRITING CENTER?INDIVIDUAL AND SMALL GROUP WRITING INSTRUCTION AND LITERACY PROGRAMMING?TO UNDERSERVED POPULATIONS BEYOND CAMPUS. IT PROVIDES AFTERSCHOOL WRITING EDUCATION FOR UNDERSERVED YOUTH AND THEIR FAMILIES IN THE HILL DISTRICT, A HISTORICALLY AFRICAN AMERICAN COMMUNITY NEAR DUQUESNE, AS WELL AS SUPPORT TO SECONDARY SCHOOL WRITING CENTERS IN THE GREATER PITTSBURGH REGION. THE ONLY WRITING CENTER IN WESTERN PENNSYLVANIA TO BRING THESE SERVICES INTO THE SURROUNDING COMMUNITY, THE CENTER?S GOAL IS TO DEVELOP THE SKILLS OF COMMUNITY MEMBERS IN AREAS THAT ARE THE HALLMARK OF A HUMANITIES EDUCATION, INCLUDING WRITTEN COMMUNICATION AND PERSONAL REFLECTION. THIS APPLICATION ADDRESSES THE CWC?S WORK TO CREATE A NEWSLETTER WITH A LOCAL SENIOR CENTER AND TO CREATE AN EDITED COLLECTION OF STORIES WITH A NON-PROFIT SUPPORTING RETURNING CITIZENS.]

ADVANCED EDUCATION NURSING TRAINEESHIP

GRADUATE RESEARCH FELLOWSHIP PROGRAM (GRFP) -THE NATIONAL SCIENCE FOUNDATION (NSF) GRADUATE RESEARCH FELLOWSHIP PROGRAM (GRFP) IS A HIGHLY COMPETITIVE FEDERAL FELLOWSHIP PROGRAM. GRFP HELPS ENSURE THE QUALITY, VITALITY, AND STRENGTH OF THE SCIENTIFIC AND ENGINEERING WORKFORCE OF THE UNITED STATES. THE PROGRAM RECOGNIZES AND SUPPORTS OUTSTANDING GRADUATE STUDENTS WHO ARE PURSUING RESEARCH-BASED MASTER'S AND DOCTORAL DEGREES IN SCIENCE, TECHNOLOGY, ENGINEERING, AND MATHEMATICS (STEM), INCLUDING STEM EDUCATION. GRFP PROVIDES THREE YEARS OF FINANCIAL SUPPORT FOR THE GRADUATE EDUCATION OF INDIVIDUALS WHO HAVE DEMONSTRATED THEIR POTENTIAL FOR SIGNIFICANT ACHIEVEMENTS IN STEM. THIS AWARD SUPPORTS THE NSF GRADUATE FELLOWS PURSUING GRADUATE EDUCATION AT THIS AWARDEE INSTITUTION. THIS AWARD REFLECTS NSF'S STATUTORY MISSION AND HAS BEEN DEEMED WORTHY OF SUPPORT THROUGH EVALUATION USING THE FOUNDATION'S INTELLECTUAL MERIT AND BROADER IMPACTS REVIEW CRITERIA.- SUBAWARDS ARE NOT PLANNED FOR THIS AWARD.

WORKSHOP ON AUTOMORPHIC FORMS AND RELATED TOPICS

COLLABORATIVE RESEARCH: CENTER FOR PHARMACEUTICAL MANUFACTURING AND FORMULATION

PROGRESS AND CHALLENGES IN CRYSTAL GROWTH, DESIGN AND CHARACTERIZATION OF MATERIALS SYMPOSIUM AT THE 2012 FALL NATIONAL AMERICAN CHEMICAL SOCIETY MEE

NO-COST EXTENSION

PROBING BLADDER PAIN PHYSIOLOGY THROUGH THE INTERROGATION OF SPECIFIC CELL TYPES IN THE AMYGDALA

NSL - BACCALAUREATE NURSING - OTHER ADMIN CHANGES

SL - PHARMACY - PD CHANGES

NITRATE ENHANCED MICROBIAL CR(VI) REDUCTION

NURSE EDUCATION, PRACTICE, QUALITY AND RETENTION - VETERANS? BACHELOR OF SCIENCE IN NURSING PROGRAM

USE OF MOLECULAR MODELING TO DETERMIN THE INTERACTION AND COMPETITION OF GASES WITHIN COALFOR CARBON DIOXIDE SEQEUSTRAT ION