Peristalsis is the main propulsive motility of the intestine and colon. The long term goal of this project has been to identify the components of the underlying reflex, the peristaltic reflex, and understand the complex interplay between luminal stimulants, paracrine agents released from mucosal enteroendocrine cells, and the neural elements which make up the sensory (afferent), interneuronal, and motor circuits of the reflex. The objective of this renewal application is to characterize the role of the neurotrophin, Brain Derived Neurotrophic Factor (BDNF), in the physiology and pathophysiology of the enteric nervous system (ENS) with regard to the regulation of the peristaltic reflex. Our preliminary studies show that proBDNF and mature BDNF (mBDNF) are present in mucosal enteroendocrine cells that contain serotonin (5-HT) and sensory neurons containing calcitonin gene-related peptide (CGRP) and substance P (SP), and that BDNF acts to enhance 5-HT and CGRP release in response to mucosal stimulation thereby enhancing peristalsis. Preliminary data also show that BDNF inhibits neurite outgrowth in adult enteric neurons. Thus, we hypothesize that the BDNF system plays an integral role in the peristaltic reflex by strengthening and enhancing the sensory limb of the peristaltic reflex circuit (Hypothesis 1) and that the BDNF system plays an integral role in the remodeling of the enteric nervous system in inflammatory states (Hypothesis 2). We will examine these hypotheses in a variety of in vitro (intact whole colonic segments, full-thickness muscle strips, variously dissected muscle strips), and culture (pure neuronal, pure smooth muscle, and nerve/muscle co-cultures) preparations. In the studies outlined in AIM 1, we will characterize the differential localization (mucosal enteroendocrine cells versus enteric and extrinsic neurons) and release of the precursor proBDNF, which has been shown to be secreted from neurons in the CNS, and the processed mature form, mBDNF. Release of BDNF will be determined in response to physiological stimuli (mucosal stroking, free fatty acids, and bile salts), to neurotransmitters (CGRP and SP), and to paracrine agents (5-HT and endocannabinoids) known to mediate or modulate the peristaltic reflex.
In AIM 2, we will use pharmacological, biochemical, and molecular tools to identify the receptors (TrkB, p75, and sortilin) and intracellular signaling pathways (PLC-gamma, PI-3-K/AKT, ERK1/2, Rho/Rock) activated by proBDNF and mBDNF, that are involved in the enhancement of peristalsis and/or inhibition of neurite growth.
In AIM 3, we will examine the production and role of proBDNF and mBDNF in mediating changes in peristalsis and remodeling of the enteric nervous system during and following recovery from colitis in animal models. As the role of neurotrophins in the physiology of the adult gut is virtually unknown, we anticipate that these studies will launch a new field of investigation and yield insight into new avenues for development of therapeutic agents for the treatment of motility disorders.
Relevance Peristalsis, the main propulsive motility of the gut, and the underlying peristaltic reflex are regulated by the complex interplay between luminal stimulants, agents released from mucosal enteroendocrine cells, and the neural elements of the enteric nervous system. Disorders of any of these components result in abnormal motility patterns that cause diarrhea or constipation and associated disturbances in absorption of nutrients and water from the gut. Based on our preliminary data, we propose to characterize the effects of a new type of agent, the neurotrophin Brain Derived Neurotrophic Factor (BDNF), on peristalsis in normal animals and an animal model of colitis. The results would open a new field of study and point the way to new avenues of investigation for pharmacological agents to treat diarrhea and/or constipation.
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