Stress and corticotropin-releasing factor (CRF) exert a profound effect on colon secreto-motor function, primarily through CRF1 receptors. The physiological role of CRF2 in the colonic response to stress is unknown. Preliminary data show that first, pharmacological activation of peripheral CRF2 prevents CRF1-mediated stress- or CRF-induced colonic enteric neuron activation and diarrhea while blockade or deletion of CRF2 enhances the colonic motor response to stress. Second, CRF1 activation enhances visceral pain response while CRF2 activation prevents capsaicin induced primary culture lumbosacral DRG neurons Ca2+ transients. Third, CRF causes less cAMP production in cells that express both CRF1/CRF2 than in cells that expresses only CRF1. Based on these key observations, we hypothesize that in rodents, peripheral CRF2 serves as a stress-coping signal that halts stress-induced colonic motility and visceral hyperalgesia through a direct and indirect action on peripheral target cells.
Specific aim 1 will establish the physiological role of CRF2 as a stress-coping mechanism in acute and chronic stress-induced colonic motor response, through inhibition of colonic enteric neurons. This will be achieved by blockade or deletion of CRF2 as well as by blocking neurotransmitter pathways and by demonstrating that stress and extrinsic nerve stimulation induce CRF ligand release in vivo and in vitro.
Specific aim 2 will test that CRF2 prevents CRF1 mediated acetylcholine release and promotes inhibitory neurotransmitters release in longitudinal muscle myenteric plexus (LMMP) tissue and primary colonic myenteric neuron culture. The putative CRF1-CRF2 interaction in native and transfected cells will be studied to gain insight on the CRF1-CRF2 signaling cross talk.
Specific aim 3 will determine whether activation of peripheral CRF2 inhibits stress-induced visceral pain sensitization through the inhibition of pelvic afferents and lumbosacral DRG neurons by performing functional, electrophysiological and molecular assays in vivo in isolated colonic afferent preparation and in vitro DRG neurons. The elucidation of the physiological role and mechanisms through which peripheral CRF2 dampens stress- and CRF-related colonic omotor alterations and visceral hypersensitivity will have important clinical implications in functional disorders such as irritable bowel syndrome, where a link between stress, CRF1 signaling pathway and symptoms are increasingly recognized.

Public Health Relevance

TO PUBLIC HEALTH The proposed study aims at establishing that CRF2 receptor signaling in the colon functions as a stress adaptation system to maintain colonic motor and pain response homeostasis. The study has relevance to gut diseases that are triggered or exacerbated by stress, including IBS. The elucidation of the effects and mechanisms through which peripheral CRF2 activation dampen stress- or CRF-related increases in colonic motor activity and visceral pain will have important clinical implications for functional gut diseases such as IBS, for which a link between stress and symptoms are increasingly recognized.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK078676-05
Application #
8310090
Study Section
Clinical and Integrative Gastrointestinal Pathobiology Study Section (CIGP)
Program Officer
Hamilton, Frank A
Project Start
2008-08-15
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2012
Total Cost
$262,421
Indirect Cost
$54,150
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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Akiba, Yasutada; Kaunitz, Jonathan D; Million, Mulugeta (2015) Peripheral corticotropin-releasing factor receptor type 2 activation increases colonic blood flow through nitric oxide pathway in rats. Dig Dis Sci 60:858-67
Taché, Yvette; Million, Mulugeta (2015) Role of Corticotropin-releasing Factor Signaling in Stress-related Alterations of Colonic Motility and Hyperalgesia. J Neurogastroenterol Motil 21:8-24
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Vu, John P; Million, Mulugeta; Larauche, Muriel et al. (2014) Inhibition of vasoactive intestinal polypeptide (VIP) induces resistance to dextran sodium sulfate (DSS)-induced colitis in mice. J Mol Neurosci 52:37-47
Million, Mulugeta; Zhao, Jing-Fang; Luckey, Andrew et al. (2013) The newly developed CRF1-receptor antagonists, NGD 98-2 and NGD 9002, suppress acute stress-induced stimulation of colonic motor function and visceral hypersensitivity in rats. PLoS One 8:e73749
Chatzaki, Ekaterini; Anton, Peter A; Million, Mulugeta et al. (2013) Corticotropin-releasing factor receptor subtype 2 in human colonic mucosa: down-regulation in ulcerative colitis. World J Gastroenterol 19:1416-23
Yuan, Pu-Qing; Wu, S Vincent; Elliott, Julie et al. (2012) Expression of corticotropin releasing factor receptor type 1 (CRF1) in the human gastrointestinal tract and upregulation in the colonic mucosa in patients with ulcerative colitis. Peptides 38:62-9

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