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: 6564787
• 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: 2001
• 资助国家: 美国
• 起止时间: 2001-12-01 至 2002-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6564787
• 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.

细胞外弹性蛋白蛋白在 通过赋予弹性的基本特性来改善心血管系统 主动脉和动脉壁。发生的结构变化的标志 动脉粥样硬化病变的发展包括钙化和 弹性纤维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 SMC 伴随弹性蛋白合成增加 增殖。并增加其他基质成分。最后期间 资助期间，我们发现IGF-I，一种与 心血管疾病过程，增加弹性蛋白基因转录。 此外，我们还确定了参与的顺式和反式作用因子 这种反应并表明所涉及的转录因子是 普遍表达但似乎在内部发生特定的相互作用 SMC 使它们能够调节弹性蛋白转录。在 与 Ravid 博士和 Sonenshein 博士的合作我们发现 腺苷和 B-myb 调节弹性蛋白启动子活性。在现在 我们建议建立在我们之前的观察基础上的应用程序并确定 IGF-1调控弹性蛋白基因的作用和机制 在培养的 SMC 中表达。此外，我们还将追查身份 cAMP 上调的弹性蛋白转录密切相关 分为项目 1、2 和 3 提出的目标。四个具体目标是 建议实现我们的目标。目标 1 表征 DNA/蛋白质 Sp1/Sp3 与控制中的弹性蛋白启动子和 IGF-I 的相互作用 处理过的SMC。目标 2 检查 C/EBP 家族成员在 IGF-I 对弹性蛋白基因的转录控制。目标 3 描述细胞周期蛋白 E 在介导 IGF-I 调节中的作用 弹性蛋白基因转录。目标 4 阐明顺式和反式元素 参与弹性蛋白启动子活性上调的作用因子 由腺苷受体介导的 cAMP 增加。这些研究应该 提供关于弹性蛋白表达的反应的重要见解 已知伴随主动脉壁损伤的事件应进一步定义 那些导致这些反应的因素。情侣的机会 我们对计划项目内的项目 1、2 和 3 进行的研究 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 （赖氨酰氧化酶胶原蛋白）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观点 墙壁损伤。