GDNF in the Enteric Nervous System

描述(由申请人提供)： 这是一项关于KO8指导临床科学家发展奖的建议，授予拥有生理学医学博士和博士学位的内科科学家。申请者的目标是获得进行消化道神经系统研究所需的技能和概念性知识。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。申请者的目标是在学术医学中心做一名终生临床科学家。这项研究是在神经胃肠病学这一新兴且迅速发展的领域进行的。这项提案的重点是将肠道神经系统作为“肠中脑”，解决与功能性胃肠道疾病相关的神经胃肠病学的一个重要方面。功能性胃肠道疾病被认为反映了肠道神经系统的神经病理性变化，可能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。本研究旨在了解神经胶质源性神经营养因子(GDNF)在肠道神经系统中的作用。GDNF作为一种有希望的治疗方法进入科学和临床生活，可以逆转导致帕金森氏症的大脑神经元退行性变化。GDNF对大脑和周围神经系统中的神经元具有保护作用。GDNF基因的突变会导致动物和人类患上先天性巨结肠。在重组GDNF治疗试验中，帕金森病患者出现IBS样腹泻和痉挛腹痛。人体试验显示，胃肠道转运有促进动力作用的证据。这项拟议工作的总体科学目标是了解GDNF如何在“肠道中的脑”中发挥作用，改变运动和分泌功能。研究工作基于试点/可行性研究的结果，这些结果表明应用GDNF在神经元兴奋性和神经传递方面都有显著作用。实验方案设计用于：1)确定GDNF对肠神经系统神经元的电行为和突触行为的作用；2)确定GDNF作用于的肠神经元的形态类型；3)确定GDNF受体在肠神经系统中的定位和分布；4)确定其对肠神经元作用的GDNF受体亚型/S；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.