IGF-1 SIGNALING AND VASCULAR AGING

IGF-1 信号传导和血管老化

• 批准号: 6828193
• 负责人: DAVID Robert CLEMMONS
• 金额: $ 38.45万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6828193
• 关键词: age difference; aging; biological signal transduction; extracellular matrix proteins; free radical oxygen; growth factor receptors; heat shock proteins; insulinlike growth factor; integrins; laboratory mouse; ligands; longevity; molecular chaperones; protein protein interaction; transcription factor; vascular smooth muscle

The purpose of these studies is to determine the role of signaling through the growth hormone (GH) and IGF-I receptors (IGF-IR) in mediating changes in vascular aging in mice and in altering the development of neointima in response to injury. The studies will utilize mice that are either haploinsufficient for the IGF-IR or have complete elimination of the GH receptor to determine how these changes alter longevity and/or vascular aging. Smooth muscle cells (SMC) obtained from the mice that are IGF-IR (+/-) will be analyzed for changes in responsiveness both to IGF-I and to changes integrin ligand occupancy. Cells from young and old animals will be compared to determine whether these responses are altered and whether reduced IGF-I signaling alters this age-dependent change. The specific pathways to be examined will include IGF-I activation of PI-3 kinase and MAP kinase. The tyrosine phosphatase SHP-2 will be analyzed to determine whether its role in mediating IGF-I signaling is altered under these conditions. The ability of IGF-I to suppress forkhead transcription factor activity and to regulate the activation of small heatshock proteins will be examined. If defects are detected in the interaction between extracellular matrix protein stimulated signaling through the alphaVbeta3 receptor and IGF-I signaling then whether these changes lead to alterations in heatshock protein activation will be determined. Since IGF-I is known to alter SMC differentiation the propensity of cells that have reduced IGF-IR to dedifferentiate and whether their response to ECM protein modulation of differentiation is altered will be determined. Additional studies will address whether the response to vascular injury is altered in animals with reduced IGF-IR. The responses of chaperones and regulators of reactive oxygen species formation will be determined. Likewise the ability of cells that express lower IGF-IR to respond to a chronic injury such as hypercholesterolemia will be determined. Lesion morphometry will be calculated in animals that are IGF-IR (+/-) and APOE (-/-) and compared to IGF-IR (-/+) animals at both 4 and 16 months of age. Alterations that have occurred in chaperones and ROS protein function following this chronic injury stimulus will be documented and it will be determined if reduced IGF-I signaling is leading to a change in the ability in these systems to adapt to the chronic injury stimulus. In this manner we should be able to determine the interactions that occur among these three important signaling systems and how they are altered during vascular injury.

这些研究的目的是确定通过生长激素（GH）和IGF-I受体（IGF-IR）介导小鼠血管老化变化和改变损伤后新生内膜发育的信号传导作用。这些研究将利用IGF-IR单倍不足或GH受体完全消除的小鼠来确定这些变化如何改变寿命和/或血管老化。将分析从IGF-IR（+/-）小鼠中获得的平滑肌细胞（SMC）对IGF-I和整联蛋白配体占有率变化的反应性变化。将比较来自年轻和年老动物的细胞，以确定这些反应是否发生改变，以及IGF-I信号传导的减少是否会改变这种年龄依赖性变化。待检查的具体途径包括IGF-I对PI-3激酶和MAP激酶的激活。将分析酪氨酸磷酸酶SHP-2以确定 其在介导IGF-I信号传导中的作用是否在这些条件下改变。IGF-I抑制叉头转录因子活性和调节小热休克蛋白活化的能力将被检查。如果在细胞外基质蛋白刺激的通过α V β 3受体的信号传导和IGF-I信号传导之间的相互作用中检测到缺陷，则将确定这些变化是否导致热休克蛋白活化的改变。由于已知IGF-I改变SMC分化，因此将确定具有降低的IGF-IR的细胞去分化的倾向以及它们对ECM蛋白调节分化的反应是否改变。更多的研究将探讨 在IGF-IR降低的动物中，对血管损伤的反应改变。将确定分子伴侣和活性氧形成调节剂的反应。同样地，将测定表达较低IGF-IR的细胞响应慢性损伤如高胆固醇血症的能力。将计算IGF-IR（+/-）和APOE（-/-）动物的病变形态学，并与4月龄和16月龄的IGF-IR（-/+）动物进行比较。将记录这种慢性损伤刺激后发生的伴侣蛋白和ROS蛋白功能的改变，并确定是否降低IGF-I 信号传导导致这些系统适应慢性损伤刺激的能力发生变化。通过这种方式，我们应该能够确定这三个重要的信号系统之间发生的相互作用，以及它们在血管损伤过程中是如何改变的。