Crohn's disease and ulcerative colitis are clinically, immunologically and morphologically distinct forms of inflammatory bowel disease (IBD). The classic inflammatory response in ulcerative colitis patients is limited to the mucosa and submucosa. Yet, the colonic circular smooth muscle contractility is suppressed in these patients. The precise nature of the stimulus and the cellular mechanisms that suppress circular smooth muscle contractility in the absence of a clearly identified inflammatory response in the muscularis externa are not known. By contrast, transmural inflammation occurs in Crohn's disease. The circular smooth muscle contractility is suppressed also in these patients. Our overarching hypothesis is that different inflammatory mediators and cellular mechanisms suppress colonic circular smooth muscle contractility in the two forms of IBD. We will test this hypothesis in two well-established and validated animal models of inflammation, the trinitrobenzene sulfonic acid (TNBS) - induced colonic inflammation that mimics the classic features of Crohn's disease, and dextran sodium sulfate (DSS) - induced colonic inflammation that mimics those of ulcerative colitis.
Our specific aims are to investigate the: 1. Differential immune responses in the muscularis externa of the TNBS and DSS models and how the initial immune response in the mucosa sends the signal to the muscularis externa to initiate the immune response there.2. Cellular and molecular mechanisms by which the respective prominent inflammatory mediators in the muscularis externa of the TNBS and DSS models alter the expression of key cell signaling proteins in circular smooth muscle cells, which suppresses their contractility.3. Cis-regulation of genes encoding the proteins, whose suppression results in the reduction of cell contractility in the TNBS and DSS models of inflammation. The hypothesis, that motility dysfunction due to the suppression of circular smooth muscle contractility may result from different cellular and molecular mechanisms, is novel. Gut inflammation may occur due to a variety of bacterial, viral and parasitic infections as well as due to food allergies, and IBD. Colonic motility dysfunction is one of the major factors contributing to the common symptom of diarrhea in all types of inflammation. Our findings are expected to suggest that alternate therapeutic approaches may be required to normalize motility dysfunction in different types of inflammation. This situation is similar to that in the two forms of IBD;both of which develop inflammation, but their therapeutic approaches are different, because the nature of inflammatory responses in the ulcerative colitis and Crohn's disease patients are different.

Public Health Relevance

Gut inflammation may occur due to a variety of bacterial, viral and parasitic infections as well as due to food allergies, and IBD. Colonic motility dysfunction is one of the major factors contributing to the common symptom of diarrhea in all types of inflammation. Our findings are expected to suggest that alternate therapeutic approaches may be required to normalize motility dysfunction in different types of inflammation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK032346-28
Application #
8310078
Study Section
Special Emphasis Panel (ZRG1-DIG-C (02))
Program Officer
Hamilton, Frank A
Project Start
1984-04-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
28
Fiscal Year
2012
Total Cost
$314,489
Indirect Cost
$106,218
Name
University of Texas Medical Br Galveston
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
Shi, Xuan-Zheng; Sarna, Sushil K (2013) Cell culture retains contractile phenotype but epigenetically modulates cell-signaling proteins of excitation-contraction coupling in colon smooth muscle cells. Am J Physiol Gastrointest Liver Physiol 304:G337-45
Chen, J; Winston, J H; Sarna, S K (2013) Neurological and cellular regulation of visceral hypersensitivity induced by chronic stress and colonic inflammation in rats. Neuroscience 248C:469-478
Sarna, Sushil K (2013) The gold standard for interpretation of slow wave frequency in in vitro and in vivo recordings by extracellular electrodes. J Physiol 591:4373-4
Li, Qingjie; Winston, John H; Sarna, Sushil K (2013) Developmental origins of colon smooth muscle dysfunction in IBS-like rats. Am J Physiol Gastrointest Liver Physiol 305:G503-12
Winston, John H; Li, Qingjie; Sarna, Sushil K (2013) Paradoxical regulation of ChAT and nNOS expression in animal models of Crohn's colitis and ulcerative colitis. Am J Physiol Gastrointest Liver Physiol 305:G295-302
Li, Qingjie; Sarna, Sushil K (2012) Nitric oxide modifies chromatin to suppress ICAM-1 expression during colonic inflammation. Am J Physiol Gastrointest Liver Physiol 303:G103-10
Choi, Kuicheon; Chen, Jinghong; Mitra, Sankar et al. (2011) Impaired integrity of DNA after recovery from inflammation causes persistent dysfunction of colonic smooth muscle. Gastroenterology 141:1293-301, 1301.e1-3
Shi, Xuan-Zheng; Winston, John H; Sarna, Sushil K (2011) Differential immune and genetic responses in rat models of Crohn's colitis and ulcerative colitis. Am J Physiol Gastrointest Liver Physiol 300:G41-51
Winston, John H; Xu, Guang-Yin; Sarna, Sushil K (2010) Adrenergic stimulation mediates visceral hypersensitivity to colorectal distension following heterotypic chronic stress. Gastroenterology 138:294-304.e3
Shi, Xuan-Zheng; Sarna, Sushil K (2009) Homeostatic and therapeutic roles of VIP in smooth muscle function: myo-neuroimmune interactions. Am J Physiol Gastrointest Liver Physiol 297:G716-25

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