Adequate nutrition depends on the integrity of the gastrointestinal (Gl) motor apparatus. When a primary Gl motility disorder is present, such as gastroparesis and chronic idiopathic pseudo-obstruction, it is often accompanied by the inability to maintain appropriate weight. In conditions where the primary defect is not a motility disease but rather a chronic or chronic intermittent caloric deficit arising e.g. from lack of food, impaired calorie utilization or abnormal eating behaviors, impaired Gl motor function including delayed gastric emptying and dyspeptic symptoms is often seen. Thus, regardless of etiology, Gl dysmotilities may occur in any disorder and condition associated with chronic or chronic intermittent negative energy balance. It follows that the caloric deficit that occurs in severe Gl motor disorders may further aggravate the primary Gl dysmotilities and contribute to the therapeutic challenge they represent, while the dysmotilities associated with non-GI causes of calorie deficit may make refeeding more difficult. Our overall goal is to identify the cellular mechanisms whereby caloric deficit interferes with normal Gl motor functions.
Our specific aims are to investigate whether (i) gastric dysmotility in caloric restriction develops from dystrophy of key cell types of the tunica muscularis such as smooth muscle cells, interstitial cells of Cajal and enteric neurons;and whether (ii) these changes are mediated by reduced systemic and local production of insulin-like growth factor-l (IGF-1), a key trophic factor; and by a loss of protection by heme oxygenase 1 (H01) from oxidative stress, which is increased in intermittent food restriction. We will use mouse models of chronic and chronic intermittent caloric restriction with or without treatments to elevate IGF-1 and HOI levels. We will also examine gastric tissues from patients suffering from severe weight loss and in normal controls. We will utilize state-of-the-art in vivo techniques (gastric emptying breath test, small animal MRI and PET) and in vitro approaches (flow cytometry, confocal microscopy, electrophysiology, real-time RT-PCR, Western blotting) to assess gastric function and central responses and to study the tissue-, cellular, and molecular mechanisms of dysmotilities. Results from this project may provide novel adjuvant therapeutic approaches to reversing loss of key cell types causing abnormal motor function.

Public Health Relevance

Gastrointestinal (Gl) motor disorders can involve weight loss and chronic undernutrition can lead to impaired Gl motility. In this project we will study the contribution of chronic caloric deficit to Gl dysmotilities. We propose that Gl dysfunction in caloric restriction arises from loss of specific cell types. Results from this project may provide novel adjuvant therapeutic approaches to reversing loss of these cell types in Gl motility disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
5P01DK068055-10
Application #
8685961
Study Section
Special Emphasis Panel (ZDK1-GRB-9)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
10
Fiscal Year
2014
Total Cost
$238,550
Indirect Cost
$87,284
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
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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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