Scripps Research Institute

TECHNOLOGY TO EMPOWER CHANGES IN HEALTH (TECH) NETWORK PARTICIPANT TECHNOLOGIES CENTER

CONSORTIUM FOR HIV/AIDS VACCINE DEVELOPMENT

CENTER FOR HIV/AIDS VACCINE IMMUNOLOGY AND IMMUNOGEN DISCOVERY

THE COMPREHENSIVE CENTER FOR CHEMICAL PROBE DISCOVERY AND OPTIMIZATION AT SCRIPPS

CENTER FOR ANTIVIRAL MEDICINES & PANDEMIC PREPAREDNESS (CAMPP) - SUMMARY THE ONGOING COVID-19 PANDEMIC HAS BROUGHT TO LIGHT AN URGENT NEED TO ENHANCE THE THERAPEUTIC PREPAREDNESS FOR FUTURE VIRAL OUTBREAKS AND PANDEMICS. THE OVERARCHING GOAL OF THE “CENTER FOR ANTIVIRAL MEDICINES & PANDEMIC PREPAREDNESS” (CAMPP) IS THUS TO DEVELOP NOVEL STRATEGIES AND ENHANCE THE DRUG DISCOVERY PIPELINES FOR DIRECT-ACTING ANTIVIRALS AGAINST RNA VIRUSES OF PANDEMIC CONCERN. THE SPECIFIC FOCUS OF CAMPP WILL BE TO DEVELOP ANTIVIRALS AGAINST CORONAVIRUSES SARS-COV-2 (SCV2), SARS AND MERS; FLAVIVIRUSES INCLUDING ZIKA, WEST NILE AND DENGUE VIRUS; AND HEMORRHAGIC FEVER VIRUSES INCLUDING THE FILOVIRUS EBOLA, AND BUNYAVIRUSES SEVERE FEVER WITH THROMBOCYTOPENIA SYNDROME VIRUS AND LASSA VIRUS. INFECTION BY ANY OF THESE AGENTS HAS THE POTENTIAL TO CAUSE SEVERE HUMAN DISEASE WITH SIGNIFICANT MORTALITY RATES AND CURRENT OPTIONS FOR ANTIVIRAL TREATMENTS ARE LIMITED. THE ANTIVIRAL DRUG REMDESIVIR AND SEVERAL MONOCLONAL ANTIBODY TREATMENTS HAVE RECEIVED EMERGENCY USE AUTHORIZATION (EUA) FOR TREATMENT OF COVID-19, AND THE POLYMERASE INHIBITOR MOLNUPIRAVIR BY MERCK IS EXPECTED TO BE GRANTED EUA IN THE NEAR FUTURE. MONOCLONAL ANTIBODIES ARE ALSO AVAILABLE TO TREAT EBOLA VIRUS INFECTION, HOWEVER, NONE OF THESE DRUGS CAN BE ADMINISTERED ORALLY, POSING ADDITIONAL CHALLENGES IN TREATING EARLY INFECTION. THERE ARE NO APPROVED TREATMENTS FOR THE CAMPP FLAVIVIRUSES AND HEMORRHAGIC FEVER VIRUSES. TOWARD THIS END, WE HAVE ASSEMBLED A WORLD CLASS MULTIDISCIPLINARY TEAM OF INVESTIGATORS WITH EXPERTISE IN VIROLOGY OF RELEVANT VIRUSES, STRUCTURAL AND COMPUTATIONAL BIOLOGY, CHEMOPROTEOMICS, PHARMACOLOGY AND ORGANOID/ANIMAL MODELS, WHO WILL WORK CLOSELY WITH THE DRUG DEVELOPMENT EXPERTS AT THE DRUG DISCOVERY DIVISION OF THE SCRIPPS RESEARCH INSTITUTE, CALIBR, TO FURTHER THE DEVELOPMENT OF FOUR MAJOR CLASSES OF PROMISING ASSETS IN OUR DRUG DISCOVERY PIPELINE. FIRST, WE PROPOSE TO DEVELOP A POTENTIALLY BEST-IN-CLASS, ORALLY BIOAVAILABLE CORONAVIRUS PROTEASE (CLPRO) INHIBITOR FOR CORONAVIRUSES INCLUDING SCV2, FROM A LATE-STAGE DRUG ASSET UNDERGOING ADME OPTIMIZATION THAT IS EXPECTED TO ENTER IND-ENABLING STUDIES WITHIN THE NEXT THREE YEARS. SECOND, WE WILL IDENTIFY AND OPTIMIZE RNA POLYMERASE INHIBITORS FOR SCV2 AND OTHER CAMPP VIRUSES, WITH THE GOAL OF REACHING IND-ENABLING STUDIES WITHIN THE NEXT FOUR YEARS. THE THIRD FOCUS OF OUR PROPOSAL IS TO DEVELOP ANTIVIRALS AGAINST OTHER ‘DRUGGABLE’ PROTEINS ENCODED BY SCV2 AND ADDITIONAL VIRUSES POSING A PANDEMIC THREAT; THESE ASSETS INCLUDE INHIBITORS OF SCV2 HELICASE, E-PROTEIN ENCODED ION CHANNEL ACTIVITY, ENTRY AND FUSION ACTIVITIES, AND NUCLEOCAPSID, WITH THE GOAL OF OBTAINING IN VIVO PROOF-OF-CONCEPT FOR A SUBSET OF THESE MID-STAGE ASSETS. FINALLY, WE PROPOSE TO TARGET TRADITIONALLY CONSIDERED ‘UNDRUGGABLE’ NON-ENZYMATIC PROTEINS INCLUDING SCV2 AND FLAVIVIRAL STRUCTURAL PROTEINS AS WELL AS RNA STRUCTURE, TO DEVELOP NOVEL STRATEGIES FOR ANTIVIRAL DRUG DEVELOPMENT. CAMPP PROVIDES A HIGHLY INTEGRATED INFRASTRUCTURE OF INVESTIGATORS, EXPERTISE AND EXTERNAL PHARMACEUTICAL AND FOUNDING PARTNERS THAT WILL ENSURE THE CENTER’S SUCCESS IN ACHIEVING OUR GOALS AND NAVIGATING CHALLENGES OF THE DRUG DISCOVERY PROCESS.

SYSTEMS APPROACH TO IMMUNITY AND INFLAMMATION

JOINT CENTER FOR STRUCTURAL GENOMICS

CNS EFFECTS OF ALCOHOL: CELLULAR NEUROBIOLOGY

REVERSING IMMUNE DYSFUNCTION FOR HIV-1 ERADICATION - PROJECT SUMMARY ALTHOUGH THE RATE OF NEW HIV INFECTIONS HAS DECREASED, CONTAINMENT AND EVENTUAL ERADICATION OF THE HIV PANDEMIC REMAINS A TOP PRIORITY IN CONTEMPORARY BIOMEDICAL RESEARCH. ONE OF THE MAJOR CHALLENGES TO HIV CURE IS THE NEED TO RESTORE NORMAL IMMUNE FUNCTION IN ORDER TO EFFECTIVELY ELIMINATE THE ESTABLISHED VIRAL RESERVOIR. WE HAVE ASSEMBLED IN RID-HIV: “REVERSING IMMUNE DYSFUNCTION FOR HIV-1 ERADICATION”, BASIC AND CLINICAL SCIENTISTS WITH EXPERTISE IN VIROLOGY, IMMUNOLOGY, MICROBIOME BIOLOGY, EPIGENETICS, AND SYSTEMS BIOLOGY. IN ADDITION, MERCK RESEARCH LABORATORIES WILL INVEST SIGNIFICANT INTELLECTUAL, HUMAN AND MATERIAL RESOURCES TO COMPLEMENT THE EFFORTS OF THE ACADEMIC SCIENTISTS. THE RID-HIV COLLABORATORY WILL COLLECTIVELY FUNCTION TO EXPLORE THE UNDERLYING BASIS OF THE IMMUNE DYSREGULATION IN HIV-INFECTED INDIVIDUALS AND THE IMPACT IT HAS ON RESERVOIR PERSISTENCE AND VIRAL REBOUND CONTROL. WE WILL TEST FOR THE FIRST TIME SEVERAL INNOVATIVE CONCEPTS, INCLUDING IDENTIFYING EPIGENETIC MECHANISMS IMPRINTED BY THE MICROBIOME AND HOST AND BACTERIAL METABOLOMES THAT PREVENTS THE DEVELOPMENT OF EFFECTIVE INNATE AND ADAPTIVE IMMUNE RESPONSES THAT CAN CONTROL THE SIZE, QUALITY AND ANATOMICAL LOCALIZATION OF THE HIV RESERVOIR. THE OVERARCHING GOAL OF THE RID-HIV COLLABORATORY IS TO PROVIDE PRECLINICAL IN VIVO PROOF-OF- CONCEPT FOR A THERAPEUTIC PARADIGM THAT ENCOMPASSES IMMUNE RESTORATIVE TREATMENTS, USED IN CONCERT WITH ENHANCED VIRAL REACTIVATION AND ELIMINATION STRATEGIES, IN ORDER TO DELIVER A HIV-1 CURE. WE PROPOSE THREE HIGHLY INTEGRATED AND COMPLEMENTARY SCIENTIFIC RESEARCH FOCI (RFS), TO BE SUPPORTED BY RIGOROUS AND ITERATIVE MODELING OF OUTCOMES AND SHAPED BY OUR OUTREACH TO THE HIV COMMUNITY. IN RF1 WE WILL INVESTIGATE THE MECHANISMS WHEREBY HOST- AND MICROBIOME-DERIVED METABOLITES IMPACT INNATE IMMUNE RESPONSES AND INFLUENCE THE MAINTENANCE OF THE LATENT VIRAL RESERVOIR. IN RF2 WE WILL PURSUE THE HYPOTHESIS THAT IN ART/ATI CLINICAL COHORTS, METABOLITES THAT GOVERN INNATE IMMUNITY SHAPE THE ADAPTIVE IMMUNE RESPONSES THAT COULD PREVENT VIRAL REBOUND UPON TREATMENT INTERRUPTION. IN ADDITION, WE WILL EVALUATE THE CAPACITY OF ENGINEERED ALLOGENIC STEM MEMORY T CELLS TO PROVIDE SUPERIOR COGNATE HELP TO PROMOTE THE EFFECTOR FUNCTIONS OF ANTIVIRAL CD8 T CELLS, AND WILL ASSESS THE ABILITY OF FDA-APPROVED AND NOVEL IMMUNE MODULATORS TO RESET THIS BASELINE IMMUNE DYSFUNCTION AND ENHANCE THE FUNCTION OF THIS NOVEL CELL THERAPY PRODUCT. IN RF 3 WE WILL OPTIMIZE A BEST-IN-CLASS LATENCY REVERSAL AGENT (LRA) AND IDENTIFY CLINICAL-STAGE MOLECULES WITH SYNERGISTIC LRA ACTIVITY. CLEARANCE OF REACTIVATED CELLS WILL BE ENHANCED USING A NOVEL STRATEGY FOR NK CELL RECRUITMENT AND BY GENETICALLY MODIFYING B CELLS TO PRODUCE BROADLY NEUTRALIZING HIV-1 ANTIBODIES THAT ENHANCE RESERVOIR CLEARANCE. FINALLY, GENE EDITING WILL BE DEPLOYED FOR IN VIVO TARGETING AND ELIMINATION OF LATENT PROVIRUS NOT AMENABLE TO LRAS. THE OUTCOMES OF STUDIES IN RF1, RF2 AND RF3 WILL ENABLE THE SYNTHESIS OF A PREDICTIVE MATHEMATICAL MODEL TO ESTABLISH THE MOST LIKELY COMBINATIONS OF THERAPIES TO ACHIEVE AN HIV-1 CURE, AND WHICH WILL BE TESTED IN A CAPSTONE AIM TO ESTABLISH PROOF-OF-CONCEPT FOR THESE STRATEGIES IN NHP MODELS AND TO ENABLE TRANSLATION TO THE CLINIC.

CONSORTIUM FOR IMMUNOTHERAPEUTICS AGAINST VIRAL HEMORRHAGIC FEVERS

CONSORTIUM FOR VIRAL SYSTEMS BIOLOGY (CVISB)

SCRIPPS TRANSLATIONAL SCIENCE INSTITUTE

SCRIPPS CLINICAL AND TRANSLATIONAL SCIENCE HUB - PROJECT SUMMARY / ABSTRACT THE SCRIPPS RESEARCH TRANSLATIONAL INSTITUTE (SRTI) IS THE FOUNDATION FOR THE SCRIPPS HUB AND IS DEDICATED TO ACCELERATING SCIENCE THAT WILL IMPROVE HUMAN HEALTH. SRTI’S EMPHASIS ON GENOMICS, DIGITAL MEDICINE, AND INFORMATICS/ANALYTICS FOSTERS A MULTI-DIMENSIONAL UNDERSTANDING OF INDIVIDUALIZED HUMAN HEALTH. THE SCRIPPS HUB HAS PREVIOUSLY INCLUDED THE SCRIPPS RESEARCH INSTITUTE (SR) AND SCRIPPS HEALTH (SH) AS PRINCIPAL PARTNERS, INCLUDING RADY CHILDREN’S INSTITUTE OF GENOMIC MEDICINE (RCIGM) FOR GENOMIC MEDICINE INITIATIVES AND CALIFORNIA INSTITUTE FOR MEDICAL RESEARCH (CALIBR) FOR DRUG REPURPOSING / DISCOVERY. IN THE NEW CTSA CYCLE, OUR PARTNERS HAVE EXPANDED TO INCLUDE SAN DIEGO STATE UNIVERSITY (SDSU), ENABLING US TO COMBINE FORCES IN COMPUTER SCIENCE, ARTIFICIAL INTELLIGENCE, BIOSENSORS, AND DIVERSITY INCLUSION AND EQUITY INITATIVES. SRTI’S EXPERTISE IN GENOMICS WAS HIGHLIGHTED DURING THE PANDEMIC. WE BECAME ONE OF THE COUNTRY’S MOST PRODUCTIVE SEQUENCING CENTERS FOR SARS-COV-2 BY RAPIDLY FORMING THE “SEARCH” ALLIANCE TO PROCESS SAMPLES WITH THE SAN DIEGO COUNTY DEPARTMENT OF HEALTH, UCSD, SHARP HEALTH, CALIFORNIA DEPARTMENT OF PUBLIC HEALTH, HELIX, AND OUR PARTNERS RCIGM AND SH. DIGITAL MEDICINE HAS BEEN ONE OF SRTI’S CORE STRENGTHS, HAVING PIONEERED THE FIRST REMOTE, SITE-LESS DIGITAL CLINICAL TRIAL AND NOW EXPANDING THIS METHODOLOGY TO ADDRESS MANY OTHER MEDICAL CONDITIONS SUCH AS HEALTH DURING PREGNANCY AND SLEEP DISORDERS. OUR DIGITAL TRIALS CENTER LAUNCHED THE DIGITAL ENGAGEMENT & TRACKING FOR EARLY CONTROL AND TREATMENT SCRIPPS (DETECT) STUDY, AND IN A MATTER OF WEEKS OUR TEAM WAS ABLE TO ACCURATELY PREDICT THE LIKELIHOOD OF COVID WITH SARS-COV-2 USING PASSIVELY COLLECTED RESTING HEART RATE DATA FROM WRISTBAND SENSORS AND LATER TO IDENTIFY A PHYSIOLOGIC SIGNATURE THAT CORRELATES WITH LONG COVID (POST-ACUTE SEQUELAE OR SARS-COV-2 INFECTION). THE SCRIPPS HUB WILL INNOVATE CLINICAL AND TRANSLATIONAL SCIENCE TO IMPROVE HUMAN HEALTH ACROSS THE LIFESPAN AND DIVERSE RACIAL, ETHNIC, GEOGRAPHIC AND SOCIOECONOMIC COMMUNITIES. THE HUB WILL PROVIDE A NURTURING ENVIRONMENT FOR EDUCATION, TRAINING, AND CAREER DEVELOPMENT WITH A FOCUS ON INDIVIDUALIZED HEALTH DOMAINS OF GENOMICS, DIGITAL MEDICINE, AND BIOMEDICAL INFORMATICS, TO EMPOWER TOMORROW’S DIVERSE WORKFORCE.

PROTEIN CARBOHYDRATE INTERACTIONS IN CELL COMMUNICATION

SCRIPPS TRANSLATIONAL SCIENCE INSTITUTE

JOINT CENTER FOR STRUCTURAL GENOMICS (JCSG-2)

HIV MACROMOLECULAR INTERACTIONS AND IMPACT ON VIRAL EVOLUTION OF DRUG RESISTANCE

ELICITING NEUTRALIZING ANTIBODIES AND B CELL RESPONSES USING NOVEL HIV ENV IMMUNOGENS IN NON-HUMAN PRIMATES - NEUTRALIZING ANTIBODIES ARE LIKELY TO BE REQUIRED FOR AN EFFECTIVE HIV-1 VACCINE. HOWEVER, FEW CANDIDATE VACCINES EFFICIENTLY ELICIT BROADLY NEUTRALIZING ANTIBODIES (BNABS) FOLLOWING VACCINATION. RECENTLY, THE VRC WORKING GROUP HAS ELICITED FUSION PEPTIDE-DIRECTED BNABS IN GUINEA PIGS AND NON-HUMAN PRIMATES (NHPS). SIMILARLY, WE RECENTLY ELICITED BNABS IN RABBITS FOLLOWING HETEROLOGOUS NFL (UNCLEAVED) TRIMER-LIPOSOME PRIME:BOOSTING AT SCRIPPS WHERE WE ACTIVATED B CELL RESPONSES WITH TARGETED N-GLYCAN DELETIONS IN THE PRIMING IMMUNIZATIONS (DUBROVSKAYA ET AL, IMMUNITY 2019). WE ISOLATED TWO RABBIT BNABS THAT RECAPITULATE THE SERUM ACTIVITY. THESE BNABS ARE DIRECTED AGAINST TWO DISTINCT SITES OF ENV VULNERABILITY. THE ELICITATION OF NEUTRALIZING RESPONSES WAS ENHANCED BY TARGETED N-GLYCAN DELETION, HIGH-DENSITY LIPOSOMAL ARRAY AND HETEROLOGOUS TRIMER RESTORATIVE BOOSTING ENV. IN INDEPENDENT EXPERIMENTS IN GUINEA PIGS, WE HAVE ELICITED BNABS IN MULTIPLE ANIMALS ALSO USING A N-GLYCAN DELETION, HETEROLOGOUS ENV NFL PRIME:BOOST APPROACH. THESE RECENT OUTCOMES ARE ENCOURAGING INROADS TOWARD THE SUCCESSFUL SOLUTION OF A 3-DECADE-LONG PROBLEM. THE NEW ERA OF NEAR-NATIVE TRIMERIC SPIKE MIMICS, COUPLED WITH PARTICULATE ARRAY, STRUCTURE-INFORMED DESIGN AND HIGH-RESOLUTION ANALYSIS OF ENV-SPECIFIC B CELL AND LYMPH NODE RESPONSES, AFFORD NEW OPPORTUNITIES TO MORE EFFICIENTLY ELICIT BNABS. WE PROPOSE AN INTEGRATED, MULTI-FACETED APPROACH BLENDING THE EXPERTISE OF WORLD LEADERS IN HIV ENV TRIMER DESIGN, ANALYSIS OF B CELL RESPONSES AND ABS FOLLOWING VACCINATION, NHP IMMUNE TISSUE ANALYSIS AND EM-BASED ANALYSIS OF ONGOING IMMUNE RESPONSES AND HIGH-RESOLUTION AB:TRIMER INTERACTIONS. WE WILL USE WELL-ORDERED TRIMER PRIME:BOOSTING THAT ELICITED BNABS IN RABBITS AND GUINEA PIGS TO ELICIT SUCH RESPONSES IN NHPS, TRANSLATING SUCCESS IN SMALL ANIMALS TO NHPS USING NOVEL IMMUNOGEN DESIGN AND PRESENTATION IN PROJECT 1 (WYATT) AND IMMUNIZATION OF NFL TRIMERS INTO NHPS VIA CORE B (SILVESTRI). WE WILL USE “REAL-TIME” SERUM FAB-TO-TRIMER BINDING EVALUATED BY EM POLYCLONAL IGG EPITOPE MAPPING (EMPEM) IN CORE C (WARD) IN COMPLEMENT WITH RAPID MAB NGS-BASED MAB CLONING, SEQUENCING AND FUNCTIONAL EXPRESSION IN PROJECT 2 (KARLSSON HEDESTAM). IN COLLABORATION WITH THE VRC (MASCOLA) WE WILL DEFINE EITHER NON-NEUTRALIZING MABS TO MASK UNWANTED NON-NEUTRALIZING EPITOPES OR TO BETTER DISPLAY THE EPITOPES OF CROSS-NEUTRALIZING MABS. WE WILL COMPARE NFL TRIMER-LIPOSOMES TO CELL SURFACE NFL TRIMER ARRAY EXPRESSED FROM THE EXCITING MRNA LIPID ENCAPSULATION TECHNOLOGY. WE WILL ASSESS IF IMMUNIZATION IN THE JUVENILE NHP B CELL REPERTOIRE COMPARED TO ADULT MACAQUES WILL BETTER GENERATE BNABS AS IS OBSERVED DURING HUMAN INFECTION. TO FOLLOW OUR DISCOVERY OF A TIER 2 CD4BS-DIRECTED BNAB FOLLOWING TRIMER-LIPOSOME VACCINATION, TERMED E70, WE WILL TARGET THE CD4BS BY DIRECTED NFL TRIMER DEGLYCOSYLATION IN THE NHPS. BASED ON OUR RECENT DISCOVERY OF THE VERY BROADLY NEUTRALIZING VACCINE-INDUCED MAB, 1C2, WE WILL ALSO FOCUS ON THE GP41:120 TRIMER INTERFACE. LEVERAGING THESE INITIAL LEADS, WE WILL UNDERTAKE A MULTIFACETED, CROSS-COMPONENT INTEGRATED APPROACH TO GUIDE THE ELICITATION OF BNABS IN NHPS FOLLOWING VACCINATION WITH NEAR-NATIVE, UNCLEAVED NFL ENV TRIMERS.

GENOMICS FOR KIDNEY TRANSPLANTATION

SCRIPPS TRANSLATIONAL SCIENCE INSTITUTE (UL1)

JCSG CENTER FOR INNOVATIVE MEMBRANE PROTEIN TECHNOLOGIES

HIGH RESOLUTION ANALYSIS OF ENV-DIRECTED B CELLS TO ACCELERATE VACCINE DESIGN

ADULT STEM CELLS FOR THERAPY OF VISUAL DISORDERS

STUDIES OF JOINT AGING AND OSTEOARTHRITIS

NEUTROPHIL LINEAGE IN INFLAMMATION - ABSTRACT NEUTROPHILS CONSTITUTE THE FIRST LINE OF CELLULAR DEFENSE AGAINST PATHOGENIC MICROORGANISMS. IN RESPONSE TO PRO- INFLAMMATORY CUES, UNRESTRICTED NEUTROPHIL ACTIVATION INDUCES TISSUE DAMAGE. TO AVOID DELETERIOUS EFFECTS TO THE HOST, NEUTROPHIL NUMBERS, ACTIVATION, AND LIFESPAN MUST BE TIGHTLY REGULATED, BUT THE MOLECULAR MECHANISMS THAT CONTROL NEUTROPHILS IN THE CONTEXT OF INFLAMMATORY DISEASE REMAIN ELUSIVE. CARDIOVASCULAR DISEASE IS THE LEADING GLOBAL CAUSE OF DEATH. RECENT EVIDENCE SUPPORTS AN IMPORTANT ROLE FOR NEUTROPHILS IN THE DEVELOPMENT OF CORONARY ARTERY DISEASE (CAD). NEUTROPHILS ARE PRESENT IN EARLY AORTIC LESIONS AND IN RUPTURE-PRONE ATHEROSCLEROTIC PLAQUES, AND A POSITIVE CORRELATION BETWEEN PLASMA LEVELS OF NEUTROPHIL SECRETORY PROTEINS AND CAD HAS BEEN ESTABLISHED, SUGGESTING THAT NEUTROPHIL EXOCYTOSIS MEDIATES DETRIMENTAL EFFECTS IN CAD. FURTHERMORE, NEUTROPHIL PRODUCTION IS INCREASED IN THE BONE MARROW IN ATHEROSCLEROTIC MODELS AND NEWLY IDENTIFIED NEUTROPHIL PRECURSORS ARE NOW KNOWN TO MEDIATE INFLAMMATION. HOW NEUTROPHIL SUBSETS CONTRIBUTE TO DISEASE PROGRESSION IN CAD HAS NOT BEEN STUDIED AND THE REGULATION OF NEUTROPHIL DIVERSITY IN DISEASE IS UNKNOWN. THE INFLAMMASOME IS AN EMERGING DRIVER IN ATHEROSCLEROSIS; HOWEVER, THE ROLE OF THE NLRP3 INFLAMMASOME ACTIVATION SELECTIVELY IN NEUTROPHILS ON ATHEROGENESIS HAS NOT BEEN STUDIED AND THE MECHANISMS REGULATING THE FUNCTIONS OF NEUTROPHIL LINEAGE CELLS IN THE CONTEXT OF INFLAMMASOME ACTIVATION AND ATHEROGENESIS REMAIN UNKNOWN. IN THIS SYNERGISTIC PROGRAM, PROJECT 1 NEUTROPHIL DEVELOPMENT DURING INFLAMMATION AND ATHEROSCLEROSIS WILL STUDY HOW NEUTROPHIL HETEROGENEITY IS MODULATED IN HUMAN SUBJECTS WITH CAD, AND HOW THE NLRP3 INFLAMMASOME IN NEUTROPHIL PROGENITORS INFLUENCES GRANULOPOIESIS AND NEUTROPHIL HETEROGENEITY IN ATHEROSCLEROSIS. PROJECT 2 NEUTROPHIL MECHANISMS DURING INFLAMMATION AND ATHEROSCLEROSIS WILL TEST THE HYPOTHESIS THAT HYPERLIPIDEMIA DIFFERENTIALLY REGULATES VESICULAR TRAFFICKING AND ASSOCIATED FUNCTIONS OF NEUTROPHIL PRECURSORS IN CAD, ESTABLISH MECHANISMS OF NLRP3-INDUCED NEUTROPHIL EXOCYTOSIS DYSREGULATION AND IMPLEMENT TRANSLATIONAL APPROACHES TO DECREASE NEUTROPHIL INFLAMMATION IN CAD. PROJECT 3 NEUTROPHIL SURVIVAL AND DEMISE DURING INFLAMMATORY STATES WILL CHARACTERIZE THE EXPRESSION AND FUNCTION OF COMPONENTS OF THE NLRP3 INFLAMMASOME IN CELLS OF THE NEUTROPHIL LINEAGE, AND WILL DEFINE THE EFFECTS OF HYPERLIPIDEMIA-INDUCED INFLAMMATION AND THE ROLES OF DEATH RECEPTOR SIGNALING IN IL-1SS PRODUCTION, MITOCHONDRIAL APOPTOSIS IN VIABILITY OF NEUTROPHIL LINEAGE CELLS, AND NECROPTOSIS SIGNALING IN ATHEROGENESIS. OUR SYNERGISTIC AND UNIQUE PROGRAM USES THE COMPLEMENTARY EXPERTISE OF THREE RENOWN RESEARCHERS, EXPERTS IN THE AREAS OF NEUTROPHIL DEVELOPMENT, NEUTROPHIL INTRACELLULAR FUNCTION REGULATION AND INFLAMMATION, TO STUDY THE CENTRAL HYPOTHESIS THAT UNRESTRICTED ACTIVATION OF NEUTROPHIL PROGENITORS AND MATURE NEUTROPHILS IS A FUNDAMENTAL PROCESS IN CARDIOVASCULAR DISEASE. THESE STUDIES WILL LEAD TO NOVEL APPROACHES TO TREAT NEUTROPHIL-MEDIATED INFLAMMATION IN CAD.

THROMBUS FORMATION AND ANTITHROMBOTIC INTERVENTION

WEST AFRICAN EMERGING INFECTIOUS DISEASE RESEARCH CENTER (WA-EIDRC)

A GENE THERAPEUTIC APPROACH TO STABLE SUPPRESSION OF HIV-1 REPLICATION

CYTOCHROME P-450 POLYMORPHISM

SCALABLE SYNTHESIS AND NEW BOND DISCONNECTIONS

HIV INTERACTIONS IN VIRAL EVOLUTION

SINGLE-MOLECULE DNA SEQUENCING WITH ENGINEERED NANOPORES

ELECTROPHYSIOLOGY OF ALCOHOL IN EXTENDED AMYGDELA

BROADLY EFFECTIVE HCV VACCINE - PROGRAM SUMMARY THE OVERARCHING GOAL OF THIS P01 PROPOSAL IS TO DEVELOP NOVEL HEPATITIS C VIRUS (HCV) VACCINE CANDIDATES THAT CAN ELICIT POTENT BROADLY NEUTRALIZING ANTIBODY RESPONSES IN IMMUNIZATION. DESPITE HIGHLY EFFECTIVE ANTIVIRAL DRUGS AGAINST HCV NOW BEING AVAILABLE, THE CONTINUOUS INCREASE IN NEW INFECTIONS UNDERSCORES THE REAL-WORLD CHALLENGES IN COMBATING THIS HUMAN INFECTION WITHOUT A VACCINE. THIS P01 PROPOSAL “BROADLY EFFECTIVE HEPATITIS C VACCINE” IS BUILT ON THE HYPOTHESIS THAT AN HCV VACCINE EFFECTIVE AGAINST DIVERSE CIRCULATING HCV STRAINS CAN BE DEVELOPED THROUGH RATIONAL ENGINEERING OF VACCINES TO ENHANCE ANTIGEN IMMUNOGENICITY AND PRESENTATION OF CONSERVED NEUTRALIZING EPITOPES, AND TO TARGET WELL-DEFINED MULTIDONOR CLASS BROADLY NEUTRALIZING ANTIBODY (BNAB) RESPONSES TO HCV. MULTIDONOR CLASS ANTIBODY RESPONSES ARE ANTIBODIES SHARING COMMON GENETIC AND FUNCTIONAL FEATURES PRODUCED IN INFECTION OR VACCINATION AT THE POPULATION LEVEL. THIS P01 PROGRAM CONSISTS OF 2 RESEARCH PROJECTS, SUPPORTED BY AN ADMIN CORE AND 2 SCIENTIFIC CORES. THE OVERALL AIMS OF THE PROGRAM ARE: (1) TO DETERMINE THE STRUCTURES OF HCV ENVELOPE GLYCOPROTEINS IMPORTANT FOR RATIONAL VACCINE DESIGN; (2) TO RATIONALLY DESIGN HCV VACCINE ANTIGENS FOR ELICITATION OF BROADLY NEUTRALIZING ANTIBODIES THAT WILL BE EFFECTIVE AGAINST DIVERSE CIRCULATING VIRAL STRAINS; (3) TO DETERMINE THE ANTIBODY RESPONSES ELICITED BY HCV VACCINE ANTIGENS IN PRECLINICAL ANIMAL MODELS. SUCCESS IN THIS RESEARCH PROGRAM WILL RESULT IN BOTH BASIC SCIENTIFIC KNOWLEDGE AND A STRONG HCV VACCINE CANDIDATE FOR FUTURE PILOT PRODUCTION AND CLINICAL TESTING.

NEURPSYCHOPHARMACOLOGY-MULTIDISCIPLINARY TRAINING

FOUR-DIMENSIONAL HETEROGENEITY OF FLUID PHASE BIOPSIES IN CANCER (4DB-CENTER)

MOLECULAR MECHANISMS LINKING AGING, ABETA PROTEOTOXICITY AND NEURODEGENERATION

DEVELOPMENT AND ADVANCEMENT OF BROAD-SPECTRUM RESPIRATORY ANTIVIRALS

MICRORNAS FOR THERAPY OF VISUAL DISORDERS

RESISTANCE DRIVEN STRUCTURAL DESIGN FOR HIV THERAPIES

CHEMICAL PROTEOMIC PLATFORMS FOR RADICALLY EXPANDING CANCER DRUGGABILITY

DEVELOPMENT OF CARBOXYL- AND AMIDE-DIRECTED C-H ACTIVATION/C-C COUPLING REACTIONS

ANTIBODY EFFECTOR FUNCTION IN PROTECTION AGAINST HIV-1

AUTODOCK SOFTWARE DEVELOPMENT AND MAINTENANCE

ROLE OF RAB27 IN GRANULOCYTE FUNCTION

INTEGRATIVE NEUROSCIENCE INITIATIVE ON ALCOHOLISM - WEST - SUPPLEMENT

MANAGING ATHEROSCLEROSIS BY MODULATING HDL FUNCTION

DEVELOPMENT OF OREXIN-1 RECEPTOR ANTAGONISTS FOR DRUG ADDICTION

CHEMOPROTEOMIC IDENTIFICATION AND THERAPEUTIC VALIDATION OF PROTEINS OF METABOLIC SIGNIFICANCE

PROTEOMIC ANALYSIS OF PLASMINOGEN RECEPTORS