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: 6127098
• 负责人: CUNMING DUAN
• 金额: $ 28.56万
• 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 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6127098
• 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（申请中的逐字描述）：动脉壁损伤 导致血管平滑肌细胞（SMC）增殖加速， 从中膜向内膜定向迁移，导致内膜增生 和增厚。这一过程对糖尿病的发病机制有重要作用。 动脉粥样硬化及相关并发症。的分子机制 在此过程中，SMC异常增殖和迁移并不理想 定义，但关键是要了解的基础上的发展 动脉粥样硬化病变胰岛素样生长因子-I（IGF-1）是一种有效的 SMC增殖和定向迁移的调节剂。促进生长和 IGF-1的趋化作用通过IGF-1受体（IGF-1 R）介导， 但同样的受体被同样的配体激活 不同的生长和趋化反应是未知的。最近我们 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IGF结合蛋白（IGFBPs），这些IGFBPs可能发挥作用， 在确定SMC是否会迁移和/或增殖中起关键作用。 对IGF-1的反应我们在这个提案中的目标是了解IGF-1， IGF-1 R和IGFBPs相互作用调节SMC增殖， 迁移这个建议的第一个目的是阐明发散增长 和IGF-1 R的配体占用激活的趋化性信号通路， SMC。第二个目标侧重于不同IGFBPs在以下方面的不同作用： 测定SMC对IGF-1的反应。定点突变也将是 产生的，以确定特定的结构基序，是必不可少的， 不同IGFBPs的不同生物学作用。第三个目标，我们将 确定细胞表面相关IGFBP 5在促进SMC迁移中的作用 向IGF-1的方向发展此外，我们将检验以下假设： IGFBP-5转位到SMC核中，并且核IGFBP-5改变SMC 运动通过一种新的机制，是独立的IGF-1 R介导的 信号通路拟议的研究将使我们了解 IGF-1、IGF-1 R和IGFBPs之间的分子相互作用， 为SMC增殖和迁移的调控提供了新的信息， 以及决定生物学特性的分子机制的概念模型。 IGF-1刺激的特定生理结果。我们相信， 完整阐明IGF-1、IGF-1 R和IGFBP作用的机制， SMC应该有很多分支，包括未来的发展 可以纠正或避免动脉粥样硬化的治疗策略， 相关并发症。