ROLE OF CORTICOTROPIN RELEASING HORMONE IN ANGIOGENESIS

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This proposal focuses on the elucidation of a novel role for corticotropin releasing hormone (CRH) as proangiogenic peptide. CRH is a 41 amino acid polypeptide initially isolated from the hypothalamus, which acts to stimulate the anterior pituitary to secrete proopiomelanocortin. Proopiomelanocortin is processed to adrenocorticotropic hormone, which stimulates the adrenal to produce cortisol. Recently, CRH has been discovered at sites of peripheral inflammation, suggesting other functions of this peptide. The nature of these other functions is not fully understood. I have previously found that CRH is a potent endothelial chemoattractant which is specific for endothelium. This discovery was based on the observation that CRH secreting tumor cells displayed a growth advantage in vivo, but not in vitro. In order to further characterize the role of CRH as an angiogenic factor, we propose the following. SPECIFIC AIM #1. To identify the specific receptors on endothelial cells through which CRH stimulates endothelial chemotaxis. SPECIFIC AIM #2. To identify the signal transduction pathways activated by CRH in endothelial cells. SPECIFIC AIM #3. To determine the effect of CRH on activation of endothelial proteases and integrin expression. Many malignant tumors express ectopic hormones, such as ACTH, human chorionic gonadotropin, and CRH, all of which stimulate cyclic AMP. The pathophysiologic role of ectopic hormone expression is unknown. The finding that CRH stimulates angiogenesis suggests a potential role of ectopic hormone secretion as a stimulus for tumor angiogenesis. Finally, peripheral CRH expression and activity may prove to be an attractive pharmacologic target in the treatment of malignant and inflammatory disorders.