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: 6389978
• 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 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6389978
• 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（来自申请书）：动脉壁损伤