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: 6411231
• 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: 2000
• 资助国家: 美国
• 起止时间: 2000-12-01 至 2001-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6411231
• 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血管紧张素转换酶中起重要作用 通过赋予心血管系统一种基本的弹性特性 主动脉和动脉壁。发生的结构性变化的一个标志 在动脉粥样硬化的发展过程中，病变包括钙化和 弹力纤维的断裂和伴随的脂质沉积 材料。矫正性血管成形术通常会导致再狭窄。 伴随着SMC的弹性蛋白合成增加 扩散。以及其他基质成分的增加。在过去的几年里 资助期，我们发现IGF-I，一种与 心血管疾病的过程，增加弹性蛋白基因转录。 此外，我们还确定了涉及的顺式和反式作用因素 这一反应表明，涉及的转录因子是 无处不在地表达，但似乎在 SMC使它们能够调节弹性蛋白转录。在……里面 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的活性。在现在 我们建议在之前观察到的基础上构建应用程序并确定 IGF-1调控弹性蛋白基因的作用及机制 在培养的SMC中表达。此外，我们还将继续进行身份鉴定 与弹性蛋白转录密切相关的cAMP上调 变成项目1、2和3提出的目标。四个具体目标是 为实现我们的目标而提出的..目的1鉴定DNA/蛋白质 对照和IGF-I中Sp1/Sp3与弹性蛋白启动子的相互作用 治疗后的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 细胞周期蛋白E在胰岛素样生长因子-I调节中的作用 弹性蛋白基因转录。目的4阐明顺式元件(S)和反式元件 弹性蛋白启动子活性上调的作用因素 由腺苷受体介导的cAMP升高。这些研究应该 对弹性蛋白表达的反应提供重要的见解 已知的伴随主动脉壁损伤的事件，并进一步应确定 这些因素导致了这些反应。结对的机会 我们与计划项目中的项目1、2和3的研究 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 (赖氨酸氧化酶，胶原)及其调节剂(B-myb，cAMP) 提供SMC对主动脉反应的全面且有意义的视图 墙壁受伤。