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.

Public Health Relevance

Work In this proposal is relevant to disorders of gastric emptying in patients with diabetes, chronic or chronic intermittent energy balances and Idiopathic conditions. We focus our efforts on Identifying dystrophic changes that occur in the gastric musculature and on duodenal-gastric feedback mechanisms that are the basis for gastric emptying disorders. We develop therapeutic strategies to prevent or reverse dystrophic changes and abnormal feed-back mechanisms to improve glycemic control and to restore gastric empting to normal values.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
5P01DK068055-09
Application #
8505006
Study Section
Special Emphasis Panel (ZDK1-GRB-9 (J1))
Program Officer
Hamilton, Frank A
Project Start
2004-09-30
Project End
2015-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
9
Fiscal Year
2013
Total Cost
$1,406,522
Indirect Cost
$514,541
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Cipriani, Gianluca; Gibbons, Simon J; Verhulst, Pieter-Jan et al. (2016) Diabetic Csf1(op/op) mice lacking macrophages are protected against the development of delayed gastric emptying. Cell Mol Gastroenterol Hepatol 2:40-47
Rajan, Elizabeth; Gostout, Christopher J; Wong Kee Song, Louis M et al. (2016) Innovative gastric endoscopic muscle biopsy to identify all cell types, including myenteric neurons and interstitial cells of Cajal in patients with idiopathic gastroparesis: a feasibility study (with video). Gastrointest Endosc 84:512-7
Cipriani, Gianluca; Gibbons, Simon J; Kashyap, Purna C et al. (2016) Intrinsic Gastrointestinal Macrophages: Their Phenotype and Role in Gastrointestinal Motility. Cell Mol Gastroenterol Hepatol 2:120-130.e1
Nelson, A D; Camilleri, M; Acosta, A et al. (2016) Effects of ghrelin receptor agonist, relamorelin, on gastric motor functions and satiation in healthy volunteers. Neurogastroenterol Motil 28:1705-1713
Wang, Zhiquan; Zhang, Honglian; Liu, Ji et al. (2016) USP51 deubiquitylates H2AK13,15ub and regulates DNA damage response. Genes Dev 30:946-59
Yan, Huihuang; Tian, Shulan; Slager, Susan L et al. (2016) Genome-Wide Epigenetic Studies in Human Disease: A Primer on -Omic Technologies. Am J Epidemiol 183:96-109
Choi, Kyoung Moo; Gibbons, Simon J; Sha, Lei et al. (2016) Interleukin 10 Restores Gastric Emptying, Electrical Activity, and Interstitial Cells of Cajal Networks in Diabetic Mice. Cell Mol Gastroenterol Hepatol 2:454-467
Eisenman, S T; Gibbons, S J; Verhulst, P-J et al. (2016) Tumor necrosis factor alpha derived from classically activated "M1" macrophages reduces interstitial cell of Cajal numbers. Neurogastroenterol Motil :
Bharucha, A E; Daley, S L; Low, P A et al. (2016) Effects of hemin on heme oxygenase-1, gastric emptying, and symptoms in diabetic gastroparesis. Neurogastroenterol Motil 28:1731-1740
Halland, Magnus; Bharucha, Adil E (2016) Relationship Between Control of Glycemia and Gastric Emptying Disturbances in Diabetes Mellitus. Clin Gastroenterol Hepatol 14:929-36

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