GDNF in the Enteric Nervous System

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DESCRIPTION (provided by applicant): This is a proposal for a KO8 Mentored Clinical Scientist Development Award for a physician scientist who holds an M.D. and Ph.D. in Physiology. The applicant aims to acquire the skills and conceptual knowledge necessary for conducting research on the nervous system of the digestive tract. This requires advanced training in electrophysiological methods, fluorescent immunohistochemistry and molecular biology to be obtained during the 5-year tenure of the Award. A lifelong career as a clinician scientist in an academic medical center is the applicant's goal. The proposed research is in the new and rapidly developing field of neurogastroenterology. The focus in this proposal on the enteric nervous system as a "brain-in-the-gut" addresses an important aspect of neurogastroenterology that is related to functional gastrointestinal disorders. Functional gastrointestinal disorders are believed to reflect neuropathic changes in the enteric nervous system that may be manifest as the irritable bowel syndrome (IBS), nonulcer dyspepsia or non-cardiac chest pain. The research is directed to understanding the role of glial derived neurotropic factor (GDNF) in the enteric nervous system. GDNF came to scientific and clinical life as a promising treatment to reverse neuronal degenerative changes in the brain that lead to Parkinson's disease. GDNF is a protective factor for neurons in the brain and peripheral nervous system. Mutations in the GDNF gene leads to Hirschsprung's disease in animals and humans. Parkinsonian patients in recombinant GDNF therapy trials experienced IBS-like diarrhea and cramping abdominal pain. Human trials showed evidence of a prokinetic action on gastrointestinal transit. The general scientific aim of the proposed work is to understand how GDNF works in the "brain-in-the-gut" to alter motility and secretory functions. The investigative work is based on results of pilot/feasibility studies that show significant actions of applied GDNF on both neuronal excitability and neurotransmission. Experimental protocols are designed to: 1) determine the action of GDNF on electrical and synaptic behavior of neurons in the enteric nervous system; 2) identify the morphological types of enteric neurons on which GDNF acts; 3) determine the localization and distribution of GDNF receptors in the enteric nervous system; 4) identify subtype/s of GDNF receptors that mediate its action on enteric neurons; 5) investigate factors that influence gene expression for the GDNF receptors in enteric neurons.