Pathobiology of the Enteric System

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Disorders of gastric emptying in patients with diabetes, eating disorders and in idiopathic conditions are a significant cause of morbidity. Current approaches for effectively managing gastric emptying disorders are ineffective. The objective of this Program Project is to advance our understanding of the dystrophic changes in the gastric musculature and feed back mechanisms that are the cause of disorders of gastric emptying and gastric motor disturbances and develop strategies to prevent or reverse these changes and restore gastric emptying that are testable in human clinical trials. The scientific objectives are met through three highly Integrated projects and three cores. Project 1 (Pathobiology of Diabetic Gastroenteropathy) studies the role of HO1 in preventing the development of diabetic gastroparesis and the mechanisms that regulate HOI activity in diabetes. Project 2 (Mechanisms of Gastric Dysfunction in Chronic Caloric Restriction) studies the role of cellular dystrophy in the gastric musculature in dysmotilities associated with chronic or chronic intermittent caloric deficit and whether the dystrophic changes are mediated by reduced production of IGF-1 and HO-1. Project 3 (Neurohumoral Regulation in Diabetic Enteropathy) evaluates in clinical trials the effect of increasing HO1 expression on gastric emptying in patients with diabetes, assesses the Impact of glycemic control on gastric emptying in diabetic patients and determines the mechanism accounting for Impaired duodenal-gastric feedback responsible for impaired fundic relaxation and rapid gastric emptying. The Administrative Core A will provide leadership of all Program Project activities. The Imaging Core B will provide advanced software for rigorous quantitative analysis for in vivo and in vitro imaging, and dynamic MR imaging on the stomach in patients. The Physiological Characterization and Data Management Core C will develop and manage an Electronic Animal Research Record that makes available In a single electronic record all research data to all Program investigators. This highly-integrated Program will make significant progress toward understanding the pathobiology of the enteric system in gastric emptying disorders and translate this knowledge into new diagnostic tools and therapy.