Project Grant F31AI202517

MECHANISMS OF DENDRITIC CELL STATE REGULATION DURING GERMINAL CENTER RESPONSES - PROJECT SUMMARY/ABSTRACT VACCINES AIM TO INDUCE PATHOGEN-SPECIFIC ANTIBODIES TO PREVENT INFECTION, BUT MANY PATHOGENS EVOLVE AND ESCAPE ANTIBODY NEUTRALIZATION. THE GERMINAL CENTER IS THE SITE WHERE VACCINE-INDUCED ANTIBODIES IMPROVE IN BOTH AFFINITY AND DIVERSITY, ALLOWING THEM TO TARGET A BROADER RANGE OF RELATED INFECTIOUS AGENTS. EXTENDING THE LIFESPAN OF GERMINAL CENTERS HAS THEREFORE BECOME A COMPELLING STRATEGY TO ENHANCE VACCINE EFFICACY AGAINST FAST-MUTATING VIRUSES SUCH AS SARS-COV-2, INFLUENZA, AND HIV. YET, BEYOND A FEW WELL-CHARACTERIZED INSTANCES, THE CELLULAR MECHANISMS THAT REGULATE GERMINAL CENTER DYNAMICS REMAIN INCOMPLETELY UNDERSTOOD. THIS PROPOSAL SEEKS TO IDENTIFY THE REGULATORY PATHWAYS, PARTICULARLY THOSE AFFECTING DENDRITIC CELL BIOLOGY, THAT SHAPE GERMINAL CENTER RESPONSES, WITH THE ULTIMATE GOAL OF INFORMING NOVEL APPROACHES TO IMPROVE VACCINE EFFICACY. THE RESEARCH TRAINING PLAN COMBINES STABLISHED MURINE MODELS (AIM 1), AND IN VIVO GENETIC PERTURBATIONS (AIM 2) TO DISCOVER HOW DENDRITIC CELL STATES INFLUENCE GERMINAL CENTER MAINTENANCE. IN AIM 1, MR. FILIPE ARAUJO HOFFMANN WILL USE PHARMACOLOGICAL AND GENETICALLY ENGINEERED MOUSE MODELS TO DISSECT THE INTERPLAY BETWEEN INNATE AND ADAPTIVE IMMUNITY DURING VACCINATION. IN AIM 2, HE WILL PERFORM TARGETED GENETIC PERTURBATIONS IN DENDRITIC CELLS IN VIVO TO UNCOVER TRANSCRIPTIONAL REGULATORS THAT AFFECT GERMINAL CENTER PERSISTENCE. MR. HOFFMANN HAS DEMONSTRATED STRONG TRAINING AND PRODUCTIVITY, WITH SIX PUBLICATIONS IN HIGH- IMPACT JOURNALS SINCE 2023. HIS CAREER DEVELOPMENT PLAN IS DESIGNED TO EXPAND HIS TECHNICAL EXPERTISE, DEEPEN HIS UNDERSTANDING OF INNATE AND ADAPTIVE IMMUNE INTERACTIONS, GROW HIS SCIENTIFIC NETWORK, AND SHARPEN HIS COMMUNICATION AND MENTORING SKILLS. HE WILL BE MENTORED BY HIS SPONSOR DR. BALI PULENDRAN, CO- SPONSOR DR. ENGLEMAN, AND ADVISORS DRS. PURVESH KHATRI, ANUSHA KALBASI, AND THEODORE ROTH, WHOSE COMPLEMENTARY EXPERTISE IN COMPUTATIONAL IMMUNOLOGY, GENE EDITING, INNATE IMMUNITY, AND SYSTEMS IMMUNOLOGY WILL PROVIDE A FERTILE ENVIRONMENT FOR HIS GROWTH. THE RESEARCH ENVIRONMENT AT STANFORD IMMUNOLOGY IS EXCEPTIONAL, OFFERING ACCESS TO WORLD-CLASS CORE FACILITIES FOR ANIMAL STUDIES, CUTTING-EDGE OMICS PLATFORMS, AND MULTIPARAMETRIC FLOW CYTOMETRY. IN ADDITION, THE PULENDRAN LAB BENEFITS FROM ROBUST CLINICAL COLLABORATIONS THROUGH HOPE CLINIC AT EMORY UNIVERSITY - A CONNECTION THAT COULD MAKE CLINICAL VALIDATION OF THIS PROPOSAL'S FINDINGS USING PRIMARY HUMAN SAMPLES FEASIBLE IN THE FUTURE. OVERALL, THIS PROPOSAL IS POISED TO PRODUCE MECHANISTIC INSIGHT INTO HOW DENDRITIC CELLS CONTROL GERMINAL CENTER RESPONSES, POTENTIALLY UNCOVERING PATHWAYS THAT CAN BE TARGETED TO GENERATE MORE EFFECTIVE AND BROADLY PROTECTIVE VACCINES.