VASCULAR RECEPTORS FOR PLATELET-DERIVED GROWTH FACTOR

血管平滑肌细胞对内皮细胞的增殖反应 损伤 这一过程对病理性疾病的发展至关重要。 动脉粥样硬化斑块中可见病变，隐静脉冠状动脉 旁路移植术和腔内血管成形术后复发的狭窄 程序. 本提案的长期目标是了解 PDGF在这些增生性病变中的作用，并开发阻断PDGF的方法。 PDGF刺激在血管疾病中的作用。 考虑到 血小板衍生生长因子相关肽在其他病理过程中的可能作用， 包括致癌作用，在这些研究中获得的见解应该有 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 受体。 本项目的目的是确定 PDGF受体，绘制受体的功能结构域，阐明 PDGF作用的分子机制，并开发研究方法 PDGF受体在体内的作用。 将投入大量精力， 受体的结构、免疫学和蛋白质化学研究 因为这些可能提供阻断PDGF作用的方法。 对于这项工作，一种新的受体纯化方法， 抗磷酸酪氨酸抗体将绕过限制， 通过更常规的方法研究PDGF受体的进展。 采用免疫印迹方法和癌基因RNA的其他新方法 原位测量将用于研究PDGF受体的活化 在体内内皮损伤后的血管壁中。 因此对于 第一次，它应该是可能的研究生物化学的 有丝分裂反应在非常少量的组织。 另外的生物化学 研究计划调查的分子机制， PDGF受体将促有丝分裂刺激传递到细胞核。 最后，研究 的活检标本将集中在患者是否有不明原因的严重 动脉粥样硬化具有高反应性PDGF系统。 的结果予以 调查应使人们更好地了解 PDGF的作用，并应有助于开发新的治疗和 血管疾病的预防方法。

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.