Project Grant F32DK148022

FUNCTIONAL AND MOLECULAR DISSECTION OF VAGAL MECHANOSENSORY NEURONS REGULATING FEEDING AND GASTROINTESTINAL PHYSIOLOGY - PROJECT SUMMARY / ABSTRACT FEEDING TRIGGERS MECHANICAL FORCES SUCH AS STRETCH AND DISTENSION THROUGHOUT THE GASTROINTESTINAL TRACT, WHICH ARE DETECTED BY VAGAL AFFERENT NEURONS (VANS) AND TRANSMITTED TO THE BRAIN TO REGULATE ESSENTIAL PHYSIOLOGICAL FUNCTIONS INCLUDING GUT MOTILITY, NUTRIENT ABSORPTION, THERMOGENESIS, AND SATIETY. WHILE GASTRIC DISTENSION IS KNOWN TO SUPPRESS FOOD INTAKE AND MODULATE PHYSIOLOGICAL RESPONSES, THE MOLECULAR AND FUNCTIONAL ARCHITECTURE OF THE VAGAL MECHANOSENSORS THAT MEDIATE THESE EFFECTS REMAIN POORLY DEFINED. THIS PROPOSAL AIMS TO DISSECT THE MOLECULAR MECHANISMS BY WHICH SPECIFIC SUBTYPES OF VANS DETECT AND TRANSDUCE GASTRIC MECHANICAL STIMULI TO COORDINATE BEHAVIORAL AND AUTONOMIC OUTCOMES. MY PRELIMINARY DATA SHOWS SIGNIFICANT RESPONSE HETEROGENEITY WITHIN GASTRIC DISTENSION-SENSING VANS, AND THAT NON-OVERLAPPING SUBSETS OF THESE VANS EXPRESS PIEZO2 AND TRPA1. MY CENTRAL HYPOTHESIS IS THAT FUNCTIONALLY DISTINCT VAN SUBPOPULATIONS, DEFINED BY EXPRESSION OF CANDIDATE MECHANOTRANSDUCERS SUCH AS PIEZO2 AND TRPA1, DIFFERENTIALLY REGULATE GASTRIC DISTENSION-INDUCED RESPONSES. IN AIM 1, I WILL DETERMINE HOW PIEZO2 AND TRPA1 VANS CONTRIBUTE TO DISTENSION-INDUCED CHANGES IN FOOD INTAKE, GASTRIC EMPTYING, LOCOMOTION, TEMPERATURE, AND BLOOD GLUCOSE, USING TARGETED GENETIC ABLATION AND BEHAVIORAL ASSAYS IN AWAKE, FREELY MOVING MICE. IN AIM 2, I WILL PERFORM FUNCTIONAL IN VIVO CA2+ IMAGING OF NODOSE GANGLION NEURONS DURING GASTRIC DISTENSION AND ALIGN THESE RECORDINGS WITH POST HOC SPATIAL TRANSCRIPTOMICS TO MOLECULARLY DEFINE AND CLASSIFY ALL RESPONSIVE SUBTYPES AND IDENTIFY NEW MECHANOTRANSDUCER CANDIDATES. MECHANOTRANSDUCER CANDIDATES WILL BE VALIDATED USING CELL-BASED FUNCTIONAL ASSAYS. THIS RESEARCH WILL UNCOVER NEW MOLECULAR MECHANISMS OF GUT MECHANOSENSATION AND IDENTIFY SPECIFIC VAGAL POPULATIONS THAT REGULATE KEY PHYSIOLOGICAL AND BEHAVIORAL RESPONSES TO GASTRIC STRETCH. BY ADVANCING OUR UNDERSTANDING OF HOW THE NERVOUS SYSTEM INTERPRETS AND ENCODES MECHANICAL SIGNALS FROM THE GUT, THIS WORK COULD INFORM TARGETED STRATEGIES FOR TREATING OBESITY AND DIGESTIVE DISORDERS. ADDITIONALLY, THE PROJECT PROVIDES COMPREHENSIVE TRAINING IN IN VIVO IMAGING, NEURAL CIRCUIT MANIPULATION, AND TRANSCRIPTOMIC ANALYSIS - POSITIONING ME FOR AN INDEPENDENT RESEARCH CAREER STUDYING SENSORY PATHWAYS WITHIN THE GUT-BRAIN AXIS.