ROLE OF CORTICOTROPIN RELEASING HORMONE IN ANGIOGENESIS

这项建议侧重于阐明促肾上腺皮质激素的新作用。 释放激素(CRH)作为促血管生成多肽。CRH是一个41个氨基酸 最初从下丘脑中分离出来的酸性多肽，作用于 刺激脑垂体前叶分泌前阿片黑素皮质素。 原阿片黑素被加工成促肾上腺皮质激素， 刺激肾上腺产生皮质醇。最近，CRH已经被 在外周炎症部位发现，提示有其他功能 这种多肽。这些其他功能的性质还没有完全被理解。 我之前发现CRH是一种强大的内皮趋化因子 这是内皮细胞所特有的。这一发现是基于 促肾上腺皮质激素释放激素肿瘤细胞生长优势的观察 体内，但不是在体外。为了进一步描述CRH作为一种 对于血管生成因子，我们提出如下建议。特定目标#1。至 确定CRH通过内皮细胞上的特异性受体 刺激内皮细胞趋化。特定目标#2。要识别 CRH激活的内皮细胞信号转导通路。 目的：确定CRH对血管紧张素转换酶激活的影响。 内皮蛋白酶和整合素的表达。许多恶性肿瘤 表达异位激素，如ACTH，人绒毛膜促性腺激素， 和CRH，所有这些都刺激环磷酸腺苷。血管紧张素转换酶的病理生理作用 异位激素的表达尚不清楚。CRH刺激的研究发现 血管生成提示异位激素分泌可能作为一种 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一个有吸引力的药理靶点。 恶性和炎症性疾病。

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.