Transforming Growth Factor Betal and Arterial Disease

描述(申请人提供)：转化生长因子-β1(TGF-β1) 似乎在动脉粥样硬化的发展中起着重要作用。转化生长因子-β1是 在动脉粥样硬化的人体动脉中表达，对血管有很强的影响 细胞。然而，转化生长因子-β1是引起还是保护作用仍存在争议 抗动脉粥样硬化。这项申请包括一系列调查， 在小鼠身上进行，这将阐明转化生长因子-β1是亲还是 抗动脉粥样硬化。调查还将确定通过哪些机制 转化生长因子-β1的表达受到调控。 提出了三个具体目标：(1)确定通过哪些机制 转化生长因子-β1促进未损伤小鼠动脉内膜生长 转化生长因子-β1表达的调控机制。(2)确定是否 体壁或动脉壁升高的转化生长因子-β1可加速动脉粥样硬化的形成，并 检测转化生长因子-β1表达增加是否改变细胞外基质和脂质 蓄积、血管细胞增殖和PAI-1表达。(3)测试 Smooth中II型转化生长因子-B受体(TGFBR2)缺失的假说 肌肉细胞，伴随着转化生长因子-β1信号的丢失，延缓了 动脉粥样硬化的发展。 具体目标将使用IN的补充战略来实现 Viva基因转移到动脉壁和生殖系操纵。在目标1中， 通过基因转移增加小鼠颈动脉中转化生长因子-β1的表达 有望促进血管内膜的生长。特定的化验将确定 这种生长发生的机制。目标2和3相辅相成 胚系实现过表达和功能丧失的途径 转化生长因子-β1及其特异性受体TGFBR2的调控。在AIM 2中转化生长因子-β1 系统地(在血浆中)或局部(在 动脉壁)。在目标3中，转化生长因子-β1对动脉壁的作用是 通过干扰平滑肌细胞中的转化生长因子-β1信号而被阻断。在两个目标中2 3、手法对动脉粥样硬化形成的影响 将会被测量。 拟议的实验将确定转化生长因子-β1对血管内皮细胞表型的影响。 正常和动脉粥样硬化的动脉，阐明分子和细胞 产生这些效应的机制，并澄清这些机制 通过它来调节动脉壁中转化生长因子-β1的表达。结果是 这些调查将揭示旨在阻止 转化生长因子-β1在动脉壁上的作用是一种有希望的治疗方法 动脉粥样硬化的防治。

DESCRIPTION (provided by the applicant): Transforming growth factor-B1 (TGF-Bl) appears to play a major role in the development of atherosclerosis. TGF-Bl is expressed in atherosclerotic human arteries and has potent effects on vascular cells. However, it remains controversial whether TGF-B1 causes or protects against atherosclerosis. This application includes a series of investigations, performed in mice, that will elucidate whether TGF-B1 is pro- or anti-atherogenic. The investigations will also identify mechanisms by which TGF-B1 expression is regulated. Three specific aims are proposed: (1) To determine the mechanisms through which TGF-B1 promotes neointimal growth in uninjured mouse arteries and to identify mechanisms by which TGF-B1 expression is regulated. (2) To determine whether elevations in systemic or arterial wall TGF-Bl accelerate atherogenesis, and to test whether increased TGF-B1 expression alters extracellular matrix and lipid accumulation, vascular cell proliferation, and PAI-1 expression. (3) To test the hypothesis that loss of the type II TGF-B receptor (tgfbr2) in smooth muscle cells, with concomitant loss of TGF-B1 signaling, retards the development of atherosclerosis. The specific aims will be accomplished using the complementary strategies of in viva gene transfer to the artery wall and germ line manipulations. In aim 1, increasing TGF-B1 expression in the mouse carotid artery by gene transfer is expected to promote intimal growth. Specific assays will identify the mechanisms by which this growth occurs. Aims 2 and 3 take complementary approaches of overexpression and loss of function, achieved by germ line manipulation of the TGF-B1 and its specific receptor, tgfbr2. In aim 2 TGF-B1 expression will be increased either systemically (in plasma) or locally (in the artery wall). In aim 3, the effects of TGF-B1 on the artery wall will be blocked by disrupting TGF-B1 signaling in smooth muscle cells. In both aims 2 and 3, the effect of the manipulations on the development of atherosclerosis will be measured. The proposed experiments will define the effects of TGF-B1 on the phenotype of normal and atherosclerotic arteries, elucidate the molecular and cellular mechanisms by which these effects are produced, and clarify the mechanisms through which TGF-B1 expression in the artery wall is regulated. The results of these investigations will reveal whether strategies aimed at blocking the actions of TGF-B1 on the artery wall represent promising approaches to the prevention and treatment of atherosclerosis.