Molecular Approaches to Pathogenesis and Therapy in Human Gastroparesis

描述(由申请人提供)： 胃瘫是一种潜在的破坏性慢性疾病，对年轻女性的影响不成比例。其发病机制尚不清楚，有效的治疗方法也很少。这一领域有意义的研究一直受到以下事实的阻碍：没有一个单一的中心能看到足够多的临床表现患者；胃瘫患者的胃组织难以获得；以及对肠道神经系统和相关组织进行病理和分子分析的复杂方法普遍缺乏。这项建议的总体目标是为建立一个具有中央数据收集和分析的临床研究站点网络奠定基础，并开发和实施研究胃瘫的通用研究方案。在这方面，有三个具体目标：1.参与设计和支持胃轻瘫数据库(GPD)的开发，该数据库将用作支持本提案的其他具体目标的工具，并促进整个联盟的临床和翻译研究。我们建议将流行病学、临床、生理和结果的各种输入输入到这个数据库中，长期目标是对患者进行表型分型，即将他们分类为病理生理定义的亚集。这样的分类将有助于寻找病因，增强进行大型临床试验的能力，并最终导致更合理和有效的治疗方法的发展。2.了解胃轻瘫的病理基础，找出其发病的分子因素。这是拟议的两项临床研究中的第一项，将主要在UTMB和罗切斯特的梅奥诊所进行。在这一目标下，我们提出了一种系统的方法来研究这些患者的胃的病理变化，表征关键分子和信号通路的变化，并将它们与临床表现联系起来。我们将以前瞻性的方式收集大量胃轻瘫患者的全层胃组织，并使用最先进的方法对其进行形态和分子变化的分析，包括全基因组表达分析和蛋白质组学。3.研究针对NK1受体的新型药物治疗胃轻瘫的疗效。这是基于SP-NK1受体信号在恶心和疼痛中起主要作用的假设提出的第二项临床研究，这两种症状是胃瘫最重要的症状。在这一目标下，我们将评估新批准的NK1受体Approant对胃轻瘫患者症状的影响，并评估其对胃功能测量的影响。这些研究将深入了解胃瘫的潜在机制，并最终导致新的、更有效的治疗形式。

DESCRIPTION (provided by applicant): Gastroparesis is a potentially devastating chronic medical illness disproportionately affecting young women. Its pathogenesis remains unknown and there are few effective therapies available. Meaningful research in this area has been hampered by the fact that no single center sees enough patients across the spectrum of clinical presentation; gastric tissue from patients with gastroparesis is not readily available; and sophisticated methodology to perform pathological and molecular analysis of the enteric nervous system and related tissues is not generally available. The overall aim of this proposal is to lay the foundation for creating a network of clinical research sites with central data collection and analysis, and develop and implement common research protocols to study gastroparesis. In this respect, there are three specific aims: 1. To participate in the design and to support the development of a Gastroparesis Database (GPD) that will serve as an instrument to support the other specific aims of this proposal as well as facilitate clinical and translational research across the Consortium. We propose a variety of epidemiological, clinical, physiological and outcome inputs should go into this database, with the long-term goal of phenotyping patients i.e. classifying them into pathophysiologically defined subsets. Such a classification would then facilitate the search for etiopathogenesis, enhance the ability to do large clinical trials and ultimately lead to the development of more rational and effective therapeutic approaches. 2. To understand the pathological basis of gastroparesis and identify molecular factors involved in its pathogenesis. This is the first of two clinical studies proposed and will be primarily carried out at UTMB and the Mayo Clinic, Rochester. Under this aim we propose a systematic approach to studying the pathological changes in the stomach of these patients, characterize the changes in key molecules and signaling pathways and correlate them with the clinical presentation. We will collect full-thickness gastric tissue in a prospective manner from a large number of patients with gastroparesis and analyze them by state-of-the-art methodology for morphological and molecular changes including genome wide expression analysis and proteomics. 3. To study the efficacy of a novel drug strategy targeted against the NK1 receptor in the treatment of gastroparesis. This is the second clinical study proposed and based on the hypothesis that the SP-NK1 receptor signaling plays a major role in nausea and pain, two of the most important symptoms of gastroparesis. Under this aim we will assess the effects of the newly approved NK1 receptor, aprepitant, on symptoms in patients with gastroparesis and assess its effects on measures of gastric function. These studies will provide insight into the underlying mechanism of gastroparesis and eventually lead to new and more effective forms of therapy