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.
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.
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