Stress and immune systems are a body's defense mechanisms against psychosomatic and pathogenic challenges. The primary mediators of the stress response are: corticotropin releasing hormone, norepinephrine, glucocorticoids and the neurotransmitters of the autonomic nervous system. The inflammatory response is mediated by cytokines, chemokines and cell adhesion molecules. However, under conditions of chronic stress or uncontrolled inflammation, these adaptive systems become maladaptive. The prolonged exposure of the cells of the peripheral organs, such as the gastrointestinal tract, to these mediators alters the gene expression of key cellular proteins, leading to alteration of their function and symptomatic disease. In this regard, the prolonged exposure of proinflammatory cytokines to colonic circular smooth muscle cells suppress the expression of Cav1.2 (L-type) calcium channels, leading to reduced Ca2+ influx and cell contractility. The effects or mechanisms of altered gene expression in colonic smooth muscle cells when exposed to chronic stress mediators have not been investigated yet. Also, the interactions between the mediators of chronic stress and those of inflammation to exacerbate or precipitate colonic circular smooth muscle dysfunction are not known. Our hypotheses are: 1) The mediators of chronic stress alter the gene expression of critical signaling proteins for excitation-contraction coupling in colonic circular smooth muscle cells (RCCSMCs). This transcriptional effect of chronic stress mediators results in smooth muscle hypersensitivity to ACh and faster transit in the colon;and 2) The cellular interactions between the stress mediators and immune mediators, when both chronic stress and inflammatory insults occur concurrently or sequentially exacerbate or precipitate colonic motility dysfunction. Accordingly, the specific aims of this proposal are to: 1) identify the mediator or mediators of chronic stress that alter gene expression of specific cell signaling proteins in RCCSMCs, resulting in smooth muscle hypersensitivity;2) investigate the cell signaling pathways and transcriptional mechanisms that induce gene expression of key signaling proteins in response to the mediator or mediators of chronic stress identified in specific aim 1, and 3) to investigate the mechanisms by which chronic stress mediators exacerbate or precipitate colonic smooth muscle dysfunction due to concurrent or sequential chronic stress and inflammatory insults. Chronic stress is well known to exacerbate or precipitate the symptoms of colonic motility dysfunction in inflammatory bowel disease and irritable bowel syndrome. The findings of this proposal are expected to identify the potential molecular therapeutic approaches that may prevent or minimize the ill effects of chronic stress on colonic motility function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK079952-03
Application #
7753240
Study Section
Special Emphasis Panel (ZRG1-DIG-C (03))
Program Officer
Hamilton, Frank A
Project Start
2008-01-15
Project End
2012-12-31
Budget Start
2010-01-01
Budget End
2010-12-31
Support Year
3
Fiscal Year
2010
Total Cost
$298,980
Indirect Cost
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
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
Li, Qingjie; Sarna, Sushil K (2011) Chronic stress targets posttranscriptional mechanisms to rapidly upregulate ?1C-subunit of Cav1.2b calcium channels in colonic smooth muscle cells. Am J Physiol Gastrointest Liver Physiol 300:G154-63
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
Li, Qingjie; Sarna, Sushil K (2009) Nuclear myosin II regulates the assembly of preinitiation complex for ICAM-1 gene transcription. Gastroenterology 137:1051-60, 1060.e1-3
Choudhury, Barun K; Shi, Xuan-Zheng; Sarna, Sushil K (2009) Norepinephrine mediates the transcriptional effects of heterotypic chronic stress on colonic motor function. Am J Physiol Gastrointest Liver Physiol 296:G1238-47