Molecular Approaches to Pathogenesis and Therapy in Human Gastroparesis

人类胃轻瘫发病机制和治疗的分子方法

• 批准号: 7219441
• 负责人: PANKAJ J PASRICHA
• 金额: $ 34.13万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-15 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7219441
• 关键词: Molecular; Approaches; Pathogenesis; Therapy; Human; Molecular; Approaches; Pathogenesis; Therapy; Human

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

描述（由申请人提供）： 胃轻瘫是一种潜在毁灭性的慢性医学疾病，对年轻女性产生了不成比例的影响。它的发病机理仍然未知，几乎没有可用的有效疗法。没有一个中心在临床表现范围内看到足够的患者，这一事实使这一领域有意义的研究受到了阻碍。来自胃轻瘫患者的胃组织不容易获得。通常不提供对肠神经系统和相关组织进行病理和分子分析的复杂方法。该提案的总体目的是为建立一个通过中央数据收集和分析的临床研究网站网络奠定基础，并开发和实施共同的研究方案来研究胃轻瘫。在这方面，有三个具体的目的：1。参与设计并支持胃肉食数据库（GPD）的开发，该工具将作为支持该提案的其他特定目标的工具，并促进整个联盟的临床和翻译研究。我们提出了各种流行病学，临床，生理和结果输入，应该进入该数据库，其长期目标是将其分类为病理生理定义的子集。然后，这种分类将有助于寻找疗法发生，增强进行大型临床试验的能力，并最终导致发展更合理有效的治疗方法。 2。了解胃轻瘫的病理基础并确定其发病机理所涉及的分子因素。这是提出的两项临床研究中的第一项，将主要在UTMB和Rochester的Mayo诊所进行。在此目的下，我们提出了一种系统的方法来研究这些患者胃的病理变化，表征关键分子和信号通路的变化，并将其与临床表现相关联。我们将从大量的胃轻瘫患者中以前瞻性方式收集全厚性胃组织，并通过最先进的形态和分子变化方法分析它们，包括基因组广泛的表达分析和蛋白质组学。 3。研究针对NK1受体治疗胃轻瘫的新型药物策略的疗效。这是提出的第二项临床研究，并基于以下假设：SP-NK1受体信号传导在恶心和疼痛中起主要作用，这是胃轻瘫的两个最重要的症状。在此目的下，我们将评估新认可的NK1受体Aprepitant对胃轻瘫患者症状的影响，并评估其对胃功能测度的影响。这些研究将为胃轻瘫的潜在机制提供洞察力，并最终导致新的，更有效的治疗形式