IGF-I REGULATION OF AORTIC ELASTIN GENE EXPRESSION

IGF-I 对主动脉弹性蛋白基因表达的调节

• 批准号: 6109356
• 负责人: JUDITH A FOSTER
• 金额: $ 30.86万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-12-01 至 1999-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6109356
• 关键词: adenosine; aorta; atherosclerotic plaque; cell cycle; cyclic AMP; cyclins; elastin; gene induction /repression; genetic promoter element; genetic regulation; genetic transcription; insulinlike growth factor; intermolecular interaction; purinergic receptor; tissue /cell culture; transcription factor; vascular smooth muscle

The extracellular protein elastin plays a significant role in the cardiovascular system by imparting an essential property of elasticity to aortic and arterial walls. A hallmark of the structural changes that occur in the development of atherosclerotic lesions include calcification and fragmentation of elastic fibers and the concomitant deposition of lipid material. Corrective angioplasty often results in restenosis with an accompanying increase in elastin synthesis concomitant with SMC proliferation. and increases in other matrix components. During the last funding period, we have found that IGF-I, a modulator associated with cardiovascular disease processes, increases elastin gene transcription. Further we have identified the cis and trans-acting factors involved in this response and shown that the transcription factors involved are ubiquitously expressed but appear to undergo specific interactions within the SMC to render them capable of modulating elastin transcription. In collaboration with Dr. Ravid and Dr. Sonenshein we have found that adenosine and B-myb modulate elastin promoter activity. In the present application we propose to build on our previous observations and determine the role and mechanisms underlying the IGF-1 regulation of elastin gene expression in cultured SMC. In addition we will pursue the identification of cAMP up-regulation of elastin transcription which is intimately tied into objectives proposed by Projects 1, 2 and 3. Four specific aims are proposed to accomplish our objectives.. Aim 1 Characterize the DNA/protein interactions of Sp1/Sp3 with the elastin promoter in control and IGF-I treated SMC. Aim 2 Examine the potential role of C/EBP family members in the transcriptional control of the elastin gene by IGF-I. Aim 3 Characterize the role of the cyclin E in mediating the IGF-I regulation of elastin gene transcription. Aim 4 Elucidate the cis element(s) and trans- acting factors involved in the up-regulation of elastin promoter activity by adenosine receptor mediated increases in cAMP. These studies should provide important insight into the response of elastin expression to events known to accompany aortic wall injury and further should define those factors responsible for these responses. The opportunity to couple our studies with those of Projects 1, 2 and 3 within the Program Project will allow us to related our findings to those of other matrix molecules (lysyl oxidase collagen) and their regulators (B-myb, cAMP) thereby providing a comprehensive and meaningful view of SMC response to aortic wall injury.

细胞外蛋白弹性蛋白在细胞外基质中起重要作用。 心血管系统通过赋予弹性的基本属性， 主动脉和动脉壁。一个标志性的结构变化发生在 在动脉粥样硬化病变的发展中包括钙化， 弹性纤维的断裂和伴随的脂质沉积 材料矫正性血管成形术经常导致再狭窄， 伴随弹性蛋白合成的增加伴随SMC 增殖并增加其他基质成分。在过去 资金期间，我们发现IGF-I，一种与 心血管疾病的过程中，增加弹性蛋白基因转录。 此外，我们已经确定了参与的顺式和反式作用因子， 这种反应，并表明，涉及的转录因子是 普遍表达，但似乎经历特定的相互作用， SMC使其能够调节弹性蛋白转录。在 与Ravid博士和Sonenshein博士合作，我们发现， 腺苷和B-myb调节弹性蛋白启动子活性。本 应用程序，我们建议建立在我们以前的意见，并确定 IGF-1对弹性蛋白基因调控的作用及机制 在培养的SMC中表达。此外，我们将继续确认 弹性蛋白转录的cAMP上调， 项目1、2、3提出的目标。四个具体目标是 为了实现我们的目标...目的1鉴定DNA/蛋白质 Sp1/Sp3与对照组和IGF-I中弹性蛋白启动子的相互作用 处理SMC。目的2研究C/EBP家族成员在 IGF-I对弹性蛋白基因的转录调控。目标3 描述细胞周期蛋白E在介导IGF-I调节细胞周期中的作用。 弹性蛋白基因转录。目的4解析顺式和反式结构单元 参与弹性蛋白启动子活性上调的作用因子 腺苷受体介导的cAMP增加。这些研究应 提供了重要的洞察弹性蛋白表达的反应， 已知伴随主动脉壁损伤的事件，应进一步定义 这些反应的原因。有机会结合 我们的研究与项目1，2和3在计划项目 将使我们能够将我们的发现与其他基质分子的发现联系起来 （赖氨酰氧化酶胶原）及其调节剂（B-myb，cAMP），从而 为SMC对主动脉瓣的反应提供了一个全面而有意义的观点， 墙伤。