Mechanisms of mechanosensation and inflammation-induced hypersensitivityin colon innervating DRG sensory neurons - Project Summary/Abstract Sensation of the gastrointestinal (GI) tract is necessary for physiologic and pathophysiologic processes. During inflammatory bowel disease (IBD), colonic inflammation induces a hypersensitivity to mechanical stimuli, triggering abdominal pain. The sensory neurons that innervate the colon and mediate abdominal pain are those with cell bodies within the dorsal root ganglia (DRG), the DRG sensory neurons. I have recently identified five genetic subtypes of DRG sensory neurons that innervate the colon and have distinct morphologies and physiologic response properties to distension. I found that one of these populations, which expresses Bmpr1b, is necessary for inflammation-induced mechanical hypersensitivity. However, which of the other populations, in particular those that are potential pain-mediating neurons, or nociceptors, are involved in mediating colonic inflammation-induced mechanical hypersensitivity is unknown. Further, mechanistic details of how mechanotransduction is mediated in colon innervating DRG neurons remain elusive, as does the mechanism through which inflammation causes mechanical hypersensitivity. In Aim 1, I propose to use neuronal electrophysiology and mouse behavior experiments to determine if two other nociceptor populations, which express Sstr2 or Adra2a, are necessary for colonic inflammation-induced hypersensitivity, to expand our knowledge of the function of colon-innervating nociceptors. In Aim 2, I will determine differences in localization of the mechanosensory ion channel Piezo2, morphologies, or ultrastructural properties of colon innervating DRG neurons with distinct mechanical force thresholds, with or without inflammation, to determine mechanisms of in vivo mechanotransduction. Finally, in Aim 3, I propose to use neuronal electrophysiology to determine the mechanism through which inflammation causes mechanical hypersensitivity, in particular through cytokine or prostaglandin signaling. These studies will reveal mechanisms of mechanosensation and inflammation-induced mechanical hypersensitivity in colon innervating sensory neurons, and perhaps reveal therapeutic targets to treat abdominal pain in IBD patients. I am a physician-scientist applying for a K08 with the long-term goal of becoming a tenure-track, independent laboratory investigator and academic clinician. I envision developing a research program focused on the mechanisms through which GI tract innervating sensory neurons respond to diverse stimuli to control physiologic and pathophysiologic processes. During my proposed K08 research training, I will perform mentored research in the lab of Dr. David Ginty in the Department of Neurobiology at Harvard Medical School (HMS), a world expert in the field of peripheral neurobiology, while completing my clinical gastroenterology training at Massachusetts General Hospital (MGH). I have assembled an expert scientific advisory committee to help guide my K08 research and career development, including Dr. Ramnik Xavier (MGH), Dr. Arlene Sharpe (HMS), and Dr. Clifford Woolf (Children’s Hospital). I will also collaborate with and receive input from Dr. Steve Liberles (HMS) and Dr. Isaac Chiu (HMS). I believe that training at HMS and MGH, both world-class research and clinical environments, along with additional conferences and coursework will help me achieve my long-term career ambitions.
