ROLE OF CORTICOTROPIN RELEASING HORMONE IN ANGIOGENESIS

这项建议的重点是阐明一个新的作用，促肾上腺皮质激素 释放激素（CRH）作为促血管生成肽。CRH是41个氨基酸 最初从下丘脑分离的酸性多肽，其作用是 刺激垂体前叶分泌阿黑皮素原。 阿黑皮素原被加工成促肾上腺皮质激素， 刺激肾上腺分泌皮质醇近日，CRH在 在外周炎症部位发现，表明了其他功能， 这个肽。这些其他功能的性质尚未完全了解。 我以前发现CRH是一种有效的内皮化学引诱物 其特异于内皮。这一发现是基于 观察到分泌CRH的肿瘤细胞在体内表现出生长优势， 体内，但不是体外。为了进一步描述CRH作为 血管生成因子，我们建议如下。具体目标#1.到 确定CRH通过内皮细胞上的特异性受体 刺激内皮趋化性。具体目标#2.识别 内皮细胞中CRH激活的信号转导通路。 具体目标#3.为了确定CRH对激活 内皮蛋白酶和整合素表达。多种恶性肿瘤 表达异位激素，如ACTH，人绒毛膜促性腺激素， 和CRH，它们都刺激环磷酸腺苷。的病理生理作用 异位激素表达未知。CRH刺激 血管生成提示异位激素分泌的潜在作用， 刺激肿瘤血管生成。最后，外周CRH表达和 活性可能被证明是治疗中有吸引力的药理学靶点 恶性和炎症性疾病的症状。

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.