GDNF in the Enteric Nervous System

肠神经系统中的 GDNF

• 批准号: 6677963
• 负责人: YUN XIA
• 金额: $ 13.01万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6677963
• 关键词: autonomic nervous system; biological signal transduction; cell biology; cell morphology; digestive system; electrophysiology; gastritis; gastrointestinal motility /pressure; gene expression; growth factor receptors; guinea pigs; immunocytochemistry; irritable bowel syndrome; molecular cloning; neural transmission; neurons; neuropathology; neuropharmacology; neurotransmitters; neurotrophic factors; protein localization; protein quantitation /detection; protein structure function; secretion; western blottings

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.

描述（由申请人提供）： 这是KO8指导的临床科学家发展奖的一项建议，该奖项是一位医学博士学位和博士学位的医师科学家的建议。生理学。申请人旨在获取有关消化道神经系统进行研究所需的技能和概念知识。这需要在奖励的5年期间获得电生理方法，荧光免疫组织化学和分子生物学的高级培训。申请人的目标是学术医学中心的临床科学家的终身职业。拟议的研究是在神经胃肠病学的新的，快速发展的领域。这项建议将肠神经系统作为“脑中的大脑”的重点是与功能性胃肠道疾病有关的神经胃肠病学的重要方面。据信功能性胃肠道疾病反映了肠神经系统中的神经性变化，可能表现为肠易激综合征（IBS），非胰腺消化不良或非心脏胸痛。这项研究旨在了解神经胶质衍生的神经性因子（GDNF）在肠神经系统中的作用。 GDNF进入了科学和临床生活，作为一种有希望的治疗方法，可以逆转大脑的神经元退行性变化，从而导致帕金森氏病。 GDNF是大脑和周围神经系统中神经元的保护因素。 GDNF基因中的突变导致动物和人类的赫希斯普伦病。重组GDNF治疗试验中的帕金森氏症患者经历了IBS样性腹泻和痉挛性腹痛。人类试验显示了对胃肠道转移作用的原始作用的证据。拟议工作的一般科学目的是了解GDNF在“脑中的大脑”中如何工作以改变运动和分泌功能。调查工作基于试验/可行性研究的结果，该研究表明，应用GDNF对神经元兴奋性和神经传递的重大作用。实验方案的设计为：1）确定GDNF对肠神经系统中神经元电气和突触行为的作用； 2）确定GDNF作用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）确定介导其对肠神经元作用的GDNF受体的亚型/s； 5）研究影响肠神经元中GDNF受体基因表达的因素。