Homeostasis between epithelial and immune systems and intestinal microbiota is important in controlling the organism's responses to inflammatory stimuli. Cathelicidin is an endogenous peptide that possesses anti- microbial functions. It constitutes a part of the overall innate immune response to protect the host against infection. Recent evidence suggests that cathelicidins (LL-37 in humans and mCRAMP in mice) may modulate responses in inflammation, apoptosis and angiogenesis. However, very little information is available to support a role of cathelicidin in intestinal inflammation. Results from our preliminary studies indicate that cathelicidins and expression of their receptors are increased in the colon of IBD patients and mouse models of colitis, but the particular cells secreting cathelicidin during intestinal inflammation are not known yet. Moreover, short-term administration of mouse cathelicidin (mCRAMP) relieves many aspects of trinitrobenzene sulphonic acid- induced colitis in mice. Therefore, we hypothesize that the inflamed colon releases molecules that stimulate cathelicidin expression from epithelial cells and/or immune cells but these moderately increased cathelicidin levels in the intestine may not be sufficient to counteract severe inflammation. Thus exogenous cathelicidin administration may be necessary to counteract colonic inflammation.
In aim 1, we will characterize the cellular cathelicidin expression profile in colons of IBD patients and several mouse models of acute and chronic colitis and we will examine the possibility to administer sodium butyrate to increase endogenous cathelicidin levels to reduce colitis in vivo.
Aim 2 will examine the in vivo therapeutic effects of short- and long-term administration of cathelicidin in mouse models of acute and chronic colonic inflammation. Experiments in aim 3 will determine the anti-angiogenic and anti-fibrogenic role of cathelicidin in cultured human intestinal microvascular endothelial cells and fibroblasts. In summary, our proposed experiments will provide important insights into the role of cathelicidins in the pathophysiology of intestinal inflammation and IBD and the mechanisms by which cathelicidins modulate colonic inflammation.

Public Health Relevance

Our research proposal will examine an important and pathophysiologically relevant research topic, namely the role of cathelicidins in intestinal inflammation. Results from our studies will provide insights of the pathophysiology of inflammatory bowel disease and evaluate the therapeutic potential of cathelicidins in intestinal inflammation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01DK084256-03
Application #
8308685
Study Section
Special Emphasis Panel (ZDK1-GRB-6 (J3))
Program Officer
Podskalny, Judith M,
Project Start
2010-07-01
Project End
2015-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
3
Fiscal Year
2012
Total Cost
$149,167
Indirect Cost
$11,049
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
Koon, Hon Wai; Ho, Samantha; Hing, Tressia C et al. (2014) Fidaxomicin inhibits Clostridium difficile toxin A-mediated enteritis in the mouse ileum. Antimicrob Agents Chemother 58:4642-50
Koon, Hon Wai; Shih, David Q; Hing, Tressia C et al. (2013) Human monoclonal antibodies against Clostridium difficile toxins A and B inhibit inflammatory and histologic responses to the toxins in human colon and peripheral blood monocytes. Antimicrob Agents Chemother 57:3214-23
Ho, Samantha; Pothoulakis, Charalabos; Koon, Hon Wai (2013) Antimicrobial peptides and colitis. Curr Pharm Des 19:40-7
Hing, Tressia C; Ho, Samantha; Shih, David Q et al. (2013) The antimicrobial peptide cathelicidin modulates Clostridium difficile-associated colitis and toxin A-mediated enteritis in mice. Gut 62:1295-305
Barrett, Robert; Zhang, Xiaolan; Koon, Hon Wai et al. (2012) Constitutive TL1A expression under colitogenic conditions modulates the severity and location of gut mucosal inflammation and induces fibrostenosis. Am J Pathol 180:636-49
Koon, Hon Wai; Shih, David Q; Chen, Jeremy et al. (2011) Cathelicidin signaling via the Toll-like receptor protects against colitis in mice. Gastroenterology 141:1852-63.e1-3