Angiogenesis is a process of the formation of new blood vessels from the existing one. It is an indispensable pathological component of numerous chronic inflammatory diseases. Recently, inflammatory bowel disease (IBD) is listed as a disorder characterized or caused by abnormal or excessive angiogenesis. However, the detailed mechanism by which angiogenesis regulates IBD has not been elucidated yet. Corticotropin-releasing hormone (CRH) is a major hypothalamic regulator of ACTH release leading to the secretion of the corticosteroids. CRH family peptides (CRH, Urocortin I, II and III) bind to CRH receptor 1 (CRHR1) and CRHR2 to exert their biological activities. In the gut, CRH alters gut motor function upon stress and increases intestinal inflammation. Recently, a new role for CRHR2 was revealed as a suppressor of vascularization by showing mice deficient for CRHR2 become hypervascularized postnatally. The long-term goal of this grant is to elucidate the molecular mechanisms of which angiogenesis contributes to the progress of IBD. The central hypothesis of this proposal is that CRH family members regulate intestinal angiogenesis. The hypothesis will be directly tested in the following specific aims.
AIM 1. Assess the role of CRHR1 and CRHR2 in colitis-associated angiogenesis in vivo.
AIM 2. Elucidate the mechanism by which CRH and Urocortin III regulate angiogenesis of intestinal endothelial cells.
AIM 3. Determine the importance of CRH and Urocortin III for production of angiogenic molecules from intestinal epithelial cells. My career goal is to become an independent researcher in the field of gastrointestinal diseases. Since I have limited experience in the field, this award will help myself [sic] well trained in IBD research. I will develop an independent research project, publish in major journals and apply for a subsequent grant support during this award period. My research environment at UCLA is outstanding due to the presence of numerous independent labs with the shared goal of understanding the mechanism of gastrointestinal diseases.

Public Health Relevance

Active inflammatory bowel disease (IBD) has an increase in abnormal blood vessels suggesting new vessel formation contributes to IBD. This study will address a role of certain factors from brain (neuropeptides) in IBD-associated vessel formation. The outcome of this study will substantially increase our understanding of the mechanism of IBD, which will lead to new therapeutic solutions to devastating intestinal diseases.

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 #
5K01DK083336-02
Application #
7780027
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Podskalny, Judith M,
Project Start
2009-04-01
Project End
2014-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
2
Fiscal Year
2010
Total Cost
$147,734
Indirect Cost
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
Aranda, Jorge; Motiejunaite, Ruta; Im, Eunok et al. (2012) Diabetes disrupts the response of retinal endothelial cells to the angiomodulator lysophosphatidic acid. Diabetes 61:1225-33
Im, Eunok; Riegler, Franz Martin; Pothoulakis, Charalabos et al. (2012) Elevated lipopolysaccharide in the colon evokes intestinal inflammation, aggravated in immune modulator-impaired mice. Am J Physiol Gastrointest Liver Physiol 303:G490-7
Gourcerol, Guillaume; Wu, S Vincent; Yuan, Pu-Qing et al. (2011) Activation of corticotropin-releasing factor receptor 2 mediates the colonic motor coping response to acute stress in rodents. Gastroenterology 140:1586-96.e6
Im, Eunok; Motiejunaite, Ruta; Aranda, Jorge et al. (2010) Phospholipase Cgamma activation drives increased production of autotaxin in endothelial cells and lysophosphatidic acid-dependent regression. Mol Cell Biol 30:2401-10
Choi, Yoon Jeong; Im, Eunok; Chung, Hyo Kyun et al. (2010) TRIF mediates Toll-like receptor 5-induced signaling in intestinal epithelial cells. J Biol Chem 285:37570-8
Im, Eunok; Rhee, Sang Hoon; Park, Yong Seek et al. (2010) Corticotropin-releasing hormone family of peptides regulates intestinal angiogenesis. Gastroenterology 138:2457-67, 2467.e1-5
Choi, Yoon Jeong; Im, Eunok; Pothoulakis, Charalabos et al. (2010) TRIF modulates TLR5-dependent responses by inducing proteolytic degradation of TLR5. J Biol Chem 285:21382-90
Im, E; Pothoulakis, C (2010) [Recent advances in Saccharomyces boulardii research]. Gastroenterol Clin Biol 34 Suppl 1:S62-70
Ma, Elise L; Choi, Yoon Jeong; Choi, Jinyoung et al. (2010) The anticancer effect of probiotic Bacillus polyfermenticus on human colon cancer cells is mediated through ErbB2 and ErbB3 inhibition. Int J Cancer 127:780-90
Im, Eunok; Choi, Yoon Jeong; Pothoulakis, Charalabos et al. (2009) Bacillus polyfermenticus ameliorates colonic inflammation by promoting cytoprotective effects in colitic mice. J Nutr 139:1848-54

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