IGF-I AND PROTEINS IN VASCULAR SMOOTH MUSCLE CELLS

血管平滑肌细胞中的 IGF-I 和蛋白质

• 批准号: 6638495
• 负责人: CUNMING DUAN
• 金额: $ 22.8万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6638495
• 关键词: binding proteins; biological signal transduction; cell migration; cell proliferation; chemotaxis; genetically modified animals; growth factor receptors; hormone regulation /control mechanism; insulinlike growth factor; intracellular transport; isozymes; laboratory mouse; mitogen activated protein kinase; phosphatidylinositol 3 kinase; protein kinase C; protein localization; protein sequence; protein transport; receptor binding; site directed mutagenesis; tissue /cell culture; vascular smooth muscle

DESCRIPTION (Verbatim from the application): Injury of the arterial wall results in accelerated vascular smooth muscle cell (SMC) proliferation and directed migration from the media to the intima, leading to intimal hyperplasia and thickening. This process contributes significantly to the pathogenesis of atherosclerosis and related complications. The molecular mechanisms underlying the abnormal SMC proliferation and migration in this process are not well defined but are key to understanding the basis of the development of atherosclerotic lesions. Insulin-like growth factor-I (IGF-1) is a potent regulator of SMC proliferation and directed migration. The growth-promoting and chemotactic actions of IGF-1 are mediated through the IGF-1 receptor (IGF-1R), but how the activation of the same receptor by the same ligand leads to distinct growth and chemotactic responses is unknown. Recently we have discovered that IGF-1 utilizes distinct signaling pathways to stimulate SMC growth and migration. Our further studies indicate that SMCs secrete several high-affinity IGF binding proteins (IGFBPs) and that these IGFBPs may play a critical role in determining whether SMCs will migrate and/or proliferate in response to IGF-1. Our goal in this proposal is to understand how IGF-1, IGF-1R, and IGFBPs interact with each other to regulate SMC proliferation and migration. The first aim in this proposal is to elucidate the divergent growth and chemotactic signaling pathways activated by ligand occupancy of IGF-1R in SMCs. The second aim focuses on the distinct roles of different IGFBPs in determining SMC response to IGF-1. Site-directed mutations will also be generated to determine the specific structural motifs that are essential for the distinct biological actions of different IGFBPs. In the third aim, we will determine the role of cell-surface-associated IGFBP5 in promoting SMC migration towards an IGF-1 gradient. Furthermore, we will test the hypothesis that IGFBP-5 is translocated into SMC nuclei and that the nuclear IGFBP-5 alters SMC motility through a novel mechanism that is independent of the IGF-1R-mediated signaling pathways. The proposed studies will lead us towards an understanding of the molecular interactions between IGF-1, IGF-1R, and IGFBPs and will provide novel information on the regulation of SMC proliferation and migration, as well as a conceptual model of the molecular mechanisms that determine the specific physiological outcomes of IGF-1 stimulation. It is our belief that a complete elucidation of the mechanisms of IGF-1, IGF-1R and IGFBP actions in SMCs should have many ramifications including the development of future therapeutic strategies that may correct or circumvent atherosclerosis and related complications.

描述(逐字摘自申请表)：动脉壁损伤 导致血管平滑肌细胞(SMC)加速增殖和 从中膜向内膜定向迁移，导致内膜增生 而且变厚了。这一过程在致病机制中起着重要作用。 动脉粥样硬化及相关并发症。潜在的分子机制 在这个过程中，SMC的异常增殖和迁移并不是很好 定义，但对于理解发展的基础 动脉粥样硬化病变。胰岛素样生长因子-1(IGF-1)是一种 SMC增殖和定向迁移的调节因子。促进增长和促进发展 IGF-1的趋化作用是通过IGF-1受体(IGF-1R)介导的， 但同样的受体如何被相同的配体激活导致 不同的生长和趋化反应尚不清楚。最近我们有 发现IGF-1利用不同的信号通路刺激SMC 增长和迁移。我们的进一步研究表明，SMC分泌几种 高亲和力胰岛素样生长因子结合蛋白(IGFBPs)，这些IGFBPs可能发挥作用 在决定SMC是否将迁移和/或扩散到 对IGF-1的反应。我们在这项提案中的目标是了解IGF-1是如何， IGF-1R和IGFBPs相互作用，调节SMC增殖和 迁移。这项提议的第一个目的是阐明不同的增长 和IGF-1R配体占位激活的趋化信号通路 SMCS。第二个目标是不同的IGFBP在 确定SMC对IGF-1的反应。定点突变也将是 生成以确定特定的结构主题，这些结构主题对于 不同IGFBPs的不同生物学作用。在第三个目标中，我们将 确定细胞表面相关的Igfbp5在促进SMC迁移中的作用 朝着IGF-1的梯度发展。此外，我们将检验这一假设 IGFBP-5转位到SMC核中，核IGFBP-5改变SMC 通过一种独立于IGF-1R介导的新机制的运动 信号通路。拟议的研究将引导我们达成一项理解 IGF-1、IGF-1R与IGFBPs和Will之间的分子相互作用 提供关于SMC增殖和迁移调控的新信息， 以及分子机制的概念模型，这些分子机制决定了 IGF-1刺激的特定生理结果。我们相信，一个 完整阐明胰岛素样生长因子-1、胰岛素样生长因子-1R和胰岛素样生长因子结合蛋白的作用机制 SMCS应该有许多影响，包括未来的发展 可纠正或绕过动脉粥样硬化和 相关并发症。