Project Grant K99DK138295

NOCICEPTOR REGULATION OF INTESTINAL INFLAMMATION AND TISSUE PROTECTION - PROJECT SUMMARY RESEARCH: INFLAMMATORY BOWEL DISEASES (IBD) ARE A GROUP OF CHRONIC INFLAMMATORY DISEASES OF THE GASTROINTESTINAL TRACT THAT AFFECT OVER 3 MILLION AMERICANS. ABDOMINAL PAIN IS A COMMON SYMPTOM OF IBD, BUT THE ROLE OF PAIN-SENSING NOCICEPTOR NEURONS IN REGULATING THE INFLAMMATORY PROCESS IS LARGELY UNKNOWN. BASED ON MY PUBLISHED AND NEW PRELIMINARY DATA, I HYPOTHESIZE THAT NOCICEPTOR SENSORY NEURONS AND NEUROPEPTIDES ARE TISSUE-PROTECTIVE, BUT BECOME DYSREGULATED IN THE CONTEXT IBD, AND SUBSEQUENTLY DRIVE PATHOLOGICAL ADAPTIVE IMMUNITY AND ALTERATIONS TO THE MICROBIOTA THAT FACILITATE INTESTINAL INFLAMMATION AND IMPAIR TISSUE REPAIR. THIS PROPOSAL AIMS TO THOROUGHLY INVESTIGATE THE REGULATION OF INTESTINAL INFECTION AND INFLAMMATION BY NOCICEPTOR SENSORY NEURONS AND DETERMINE THE DETAILED UNDERLYING CELLULAR AND MOLECULAR MECHANISMS USING INNOVATIVE AND INTERDISCIPLINARY APPROACHES FROM NEUROBIOLOGY, GASTROENTEROLOGY, IMMUNOLOGY AND MICROBIOLOGY. THESE STUDIES WILL UNCOVER NOVEL NEURO-IMMUNE-MICROBIOTA CROSSTALK PATHWAYS AND THEIR UNIQUE ROLES IN INTESTINAL INFLAMMATION AND TRANSFORM OUR UNDERSTANDINGS OF HOST-MICROBE INTERACTIONS AND NEURO-IMMUNE MECHANISMS IN IBD. CAREER GOALS: MY OVERARCHING CAREER GOAL IS TO BECOME AN INDEPENDENT INVESTIGATOR AT AN ACADEMIC INSTITUTION WHERE I DECIPHER THE NEURO-IMMUNE AND NEURON-MICROBIOTA PATHWAYS THAT REGULATE INTESTINAL TOLERANCE AND INFLAMMATION AND EVENTUALLY DISCOVER NEURONAL-BASED AND MICROBIOTA-BASED DRUG TARGETS FOR IMMUNE MODULATION TO TREAT CHRONIC INFLAMMATORY DISEASES INCLUDING IBD. FURTHERMORE, I ASPIRE TO BECOME AN INSPIRATIONAL TEACHER AND OUTSTANDING MENTOR. CAREER DEVELOPMENT PLAN: TO BECOME A SUCCESSFUL INDEPENDENT INVESTIGATOR I WILL FURTHER DEVELOP VARIOUS RESEARCH, PROFESSIONAL AND PERSONAL SKILLS. THESE WILL INCLUDE FURTHER ACQUIRING EXPERTISE IN NEUROBIOLOGY AND MICROBIOLOGY TECHNIQUES, AS WELL AS FOSTERING COLLABORATIONS AND DEVELOPING SKILLS IN WRITING, MENTORING, TEACHING, COMMUNICATING AND LABORATORY MANAGEMENT. MY HOST LABORATORY AND WEILL CORNELL MEDICINE PROVIDES AN OUTSTANDING ACADEMIC ENVIRONMENT IN WHICH TRAINEES CAN FULFIL THESE CRITERIA BY PROMOTING SCIENTIFIC INTERACTIONS AND ENROLLING IN COURSES TO DEVELOP SKILLS IN SPECIALIST SCIENTIFIC AREAS, PERSONAL DEVELOPMENT AND LABORATORY MANAGEMENT. THE MENTORSHIP I WILL RECEIVE WILL BE OF THE HIGHEST STANDARD. FURTHERMORE, IN ADDITION TO MY MENTOR AND CO-MENTOR, I HAVE SUPPORT FROM A TEAM OF INDEPENDENT INVESTIGATORS WITH EXTENSIVE EXPERTISE IN AREAS THAT WILL GREATLY FACILITATE THE COMPLETION OF EXPERIMENTS PROPOSED AND MY CAREER TRANSITIONAL INTO INDEPENDENCE. CAREER DEVELOPMENT ENVIRONMENT: I WILL PERFORM THE K99 PHASE IN THE LABORATORY OF DR. DAVID ARTIS AT THE WEILL CORNELL MEDICINE, WHICH PROVIDES AN UNPRECEDENTED ENVIRONMENT IN TERMS OF THE RESOURCES AND FACILITIES AVAILABLE. WEILL CORNELL MEDICINE IS AN IDEAL ENVIRONMENT TO DEVELOP DURING THE K99 PHASE AS I PROGRESS TO BECOME A SUCCESSFUL INDEPENDENT INVESTIGATOR. THE LABORATORY HAS ACCESS TO ALL OF THE EQUIPMENT AND FACILITIES NECESSARY TO COMPLETE THE EXPERIMENTS PROPOSED IN THIS APPLICATION.