Molecular Approaches to Pathogenesis and Therapy in Human Gastroparesis

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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