Wednesday, January 15, 2025
1/15/2025
PROJECT SUMMARY There is an urgent need to develop non-addictive analgesic agents for the treatment of abdominal pain which is common in gastrointestinal disorders, such as irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD). Glutamate carboxypeptidase II (GCPII) is a metallopeptidase that is expressed throughout the central and peripheral nervous systems (CNS, PNS respectively), where it regulates glutamate neurotransmission. Glutamate is the most abundant excitatory neurotransmitter in the body and is known to be a key player in nociception and pain signaling. In fact, small molecule GCPII inhibitors have been previously demonstrated to exert potent analgesic effects in numerous rodent models of inflammatory, neuropathic and musculoskeletal pain. While GCPII’s role in CNS and PNS pain pathways are well characterized, GCPII’s expression and function have not yet been studied in the enteric nervous system. We have recently discovered that GCPII is present throughout the ENS, with prominent expression in enteroendocrine cells (EEC) of the ileum and colon. EECs are a population of cells located throughout the gastrointestinal epithelium that are responsible for sensing luminal stimuli, secreting various hormones and neurotransmitters, and that have been reported to participate in vagal afferent signaling and bi-directional gut brain axis communication. Here, we will study the biology of GCPII in EEC-associated visceral pain signaling. Our central hypothesis is that GCPII regulates EEC glutamate secretion, altering subsequent vagal afferent activation and visceral pain signaling. In Aim #1, we will develop a glutamate biosensor assay to assess GCPII’s role as a modulator of EEC glutamate secretion, including evaluation of a small molecule GCPII inhibitor, CRISPR/Cas9 knockdown and administration of an exogenous GCPII substrate. In Aim #2, we will characterize GCPII expression changes over time in an established rodent abdominal pain model and will characterize the cellular markers of EEC subpopulations expressing GCPII. In Aim #3, we will create a novel mouse with targeted deletion of GCPII in EECs, and will objectively measure visceral pain reaction in response to aversive colorectal distension stimulation to study GCPII’s role in EEC- associated visceral pain signaling in an in vivo model system. Collectively, this research will expand our knowledge regarding GCPII expression and function in visceral pain, laying the preclinical foundation for future studies to develop novel therapeutics for abdominal pain.
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