GDNF in the Enteric Nervous System

描述（由申请人提供）： 这是一项针对拥有医学博士学位的医生科学家的KO 8指导临床科学家发展奖的提案。和博士生理学。申请人旨在获得进行消化道神经系统研究所需的技能和概念知识。这需要在该奖项的5年任期内获得电生理学方法，荧光免疫组织化学和分子生物学方面的高级培训。申请人的目标是在学术医疗中心担任临床科学家。拟议的研究是在神经胃肠病学的新的和迅速发展的领域。在这个建议的重点是肠神经系统作为一个“脑在肠道”解决了一个重要方面的神经胃肠病学是有关功能性胃肠疾病。功能性胃肠疾病被认为反映了肠神经系统中的神经病理性变化，其可表现为肠易激综合征（IBS）、非溃疡性消化不良或非心源性胸痛。本研究旨在了解胶质源性神经营养因子（GDNF）在肠神经系统中的作用。GDNF作为一种有希望的治疗方法进入科学和临床生活，以逆转导致帕金森病的大脑神经元退行性变化。GDNF是脑和周围神经系统中神经元的保护因子。GDNF基因突变导致动物和人类的先天性巨结肠症。重组GDNF治疗试验中的帕金森病患者经历了IBS样腹泻和痉挛性腹痛。人体试验显示了对胃肠道转运的促动力作用的证据。这项工作的总体科学目标是了解GDNF如何在“肠中脑”中发挥作用，以改变运动和分泌功能。调查工作是基于试点/可行性研究的结果，显示应用GDNF对神经元兴奋性和神经传递的显着作用。设计实验方案以：1）确定GDNF对肠神经系统中神经元的电和突触行为的作用; 2）鉴定GDNF作用于其上的肠神经元的形态学类型; 3）确定GDNF受体在肠神经系统中的定位和分布; 4）鉴定介导其对肠神经元的作用的GDNF受体的亚型; 5）研究影响肠神经元GDNF受体基因表达的因素。

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.