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.
|Kendig, Derek M; Hurst, Norm R; Grider, John R (2016) Spatiotemporal Mapping of Motility in Ex Vivo Preparations of the Intestines. J Vis Exp :e53263|
|Al-Qudah, M; Alkahtani, R; Akbarali, H I et al. (2015) Stimulation of synthesis and release of brain-derived neurotropic factor from intestinal smooth muscle cells by substance P and pituitary adenylate cyclase-activating peptide. Neurogastroenterol Motil 27:1162-74|
|Kendig, D M; Grider, J R (2015) Serotonin and colonic motility. Neurogastroenterol Motil 27:899-905|
|Avetisyan, Marina; Wang, Hongtao; Schill, Ellen Merrick et al. (2015) Hepatocyte Growth Factor and MET Support Mouse Enteric Nervous System Development, the Peristaltic Response, and Intestinal Epithelial Proliferation in Response to Injury. J Neurosci 35:11543-58|
|Kendig, Derek M; Hurst, Norman R; Bradley, Zachary L et al. (2014) Activation of the umami taste receptor (T1R1/T1R3) initiates the peristaltic reflex and pellet propulsion in the distal colon. Am J Physiol Gastrointest Liver Physiol 307:G1100-7|
|Qiao, Zhongwei; Xia, Chunmei; Shen, Shanwei et al. (2014) Suppression of the PI3K pathway in vivo reduces cystitis-induced bladder hypertrophy and restores bladder capacity examined by magnetic resonance imaging. PLoS One 9:e114536|
|Al-Qudah, M; Anderson, C D; Mahavadi, S et al. (2014) Brain-derived neurotrophic factor enhances cholinergic contraction of longitudinal muscle of rabbit intestine via activation of phospholipase C. Am J Physiol Gastrointest Liver Physiol 306:G328-37|
|Anderson Jr, Charles D; Kendig, Derek M; Al-Qudah, Mohammad et al. (2014) Role of various kinases in muscarinic M3 receptor-mediated contraction of longitudinal muscle of rat colon. J Smooth Muscle Res 50:103-19|
|Hurst, Norm R; Kendig, Derek M; Murthy, Karnam S et al. (2014) The short chain fatty acids, butyrate and propionate, have differential effects on the motility of the guinea pig colon. Neurogastroenterol Motil 26:1586-96|
|Bala, Vanitha; Rajagopal, Senthilkumar; Kumar, Divya P et al. (2014) Release of GLP-1 and PYY in response to the activation of G protein-coupled bile acid receptor TGR5 is mediated by Epac/PLC-Îµ pathway and modulated by endogenous H2S. Front Physiol 5:420|
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