VASCULAR RECEPTORS FOR PLATELET-DERIVED GROWTH FACTOR

血管平滑肌细胞对内皮细胞的反应 受伤。这一过程是病理发展的基础。 病变见于动脉粥样硬化斑块、大隐静脉、冠状动脉 搭桥术和血管成形术后复发的狭窄 程序。这项提议的长期目标是理解 PDGF在这些增生性皮损中的表达，并开发阻断方法 血小板衍生生长因子刺激在血管疾病中的作用鉴于 PDGF相关多肽在其他病理过程中的可能作用 包括致癌，在这些研究中获得的洞察力应该是 对几种疾病的影响。 PDGF通过作用于特定的细胞表面刺激细胞分裂 感受器。该项目的目标是确定 PDGF受体，绘制该受体的功能结构域，以阐明 血小板衍生生长因子作用的分子机制及其研究进展 PDGF受体在体内的作用。将做出巨大努力，致力于 受体的结构、免疫学和蛋白质化学研究 因为这些可能会提供阻止PDGF行动的方法。 在这项工作中，一种新的受体纯化方法使用 抗磷酸酪氨酸抗体将绕过曾经阻碍 PDGF受体的常规方法研究进展。 使用免疫印迹方法和癌基因RNA的其他新方法 将使用现场测量来研究PDGF受体的激活 在活体内皮损伤后的血管壁中。因此，对于 第一次，它应该可以研究的生物化学 极少量组织中的有丝分裂反应。附加生化 目前正计划进行研究，以探讨这种疾病的分子机制。 PDGF受体将促有丝分裂的刺激传递到细胞核。最后，研究 活检样本的比例将集中在不明原因的重症患者 动脉粥样硬化有一种高反应性的PDGF系统。这些研究的结果 调查应提供对基本方面的更好了解 并应有助于开发新的治疗和治疗方法 预防血管疾病的方法。

Vascular smooth muscle cells proliferate in response to endothelial injury. This process is fundamental to the development of the pathological lesions seen in atherosclerotic plaques, saphenous vein coronary artery bypass grafts, and stenoses that recur following transluminal angioplasty procedures. The long term goal of this proposal is to understand the role of PDGF in these proliferative lesions and to develop methods of blocking the effects of PDGF stimulation in vascular disease. In view of the probable role of PDGF-related peptides in other pathological processes, including carcinogenesis, the insight gained in these studies should have impact on several diseases. PDGF stimulates cell division by acting through specific cell surface receptors. The aims of this project are to determine the structure of the PDGF receptor, to map the functional domains of the receptor, to elucidate the molecular mechanism of PDGF action, and to develop approaches to study the role of the PDGF receptor in vivo. A large effort will be devoted to structural, immunological, and protein chemistry studies of the receptors since these are likely to provide approaches to block the action of PDGF. For this work a novel method of receptor purification using the antiphosphotyrosine antibodies will circumvent limitations that had impeded progress in studies of the PDGF receptor by more conventional methods. Other new approaches employing immunoblot methods and oncogene RNA measurements in situ will be used to study the activation of PDGF receptors in the blood vessel wall following endothelial injury in vivo. Thus for the first time, it should be possible to study the biochemistry of the mitogenic response in very small amounts of tissue. Additional biochemical studies are planned to investigate the molecular mechanism by which the PDGF receptor transmits mitogenic stimuli to the nucleus. Finally, studies of biopsy specimens will focus on whether patients with unexplained severe atherosclerosis have a hyper-responsive PDGF system. The results of these investigations should provide a better understanding of the basic aspects of PDGF action and should aid in the development of new therapeutic and prophylactic approaches to vascular disease.