Transforming Growth Factor Betal and Arterial Disease

性状（由申请人提供）：转化生长因子-B1（TGF-B1） 似乎在动脉粥样硬化的发展中起主要作用。TGF-β 1是 在动脉粥样硬化的人动脉中表达，并对血管 细胞然而，TGF-B1是否引起或保护， 对抗动脉粥样硬化本申请包括一系列调查， 在小鼠中进行，这将阐明TGF-β 1是否是促或 抗动脉粥样硬化这些调查还将查明 TGF-β 1的表达受到调节。 提出了三个具体目标：（1）确定机制， TGF-B1促进未损伤小鼠动脉的新生内膜生长， TGF-β 1表达的调节机制。(2)以确定是否 全身或动脉壁TGF-β 1的升高加速动脉粥样硬化形成， 检测TGF-β 1表达增加是否会改变细胞外基质和脂质 聚集、血管细胞增殖和派-1表达。(3)测试 假设II型TGF-β受体（tgfbr 2）在平滑肌细胞中的缺失 肌细胞，伴随着TGF-β 1信号的丢失，延缓了 动脉粥样硬化的发展。 具体目标将通过以下方面的补充战略来实现： viva基因转移到动脉壁和生殖系操作。在目标1中， 通过基因转移增加小鼠颈动脉中TGF-β 1的表达， 促进内膜生长。特定的检测将识别 这种增长的机制。目标2和3采取互补措施 过表达和功能丧失的途径，通过生殖系 TGF-B1及其特异性受体tgfbr 2的操纵。在aim 2中，TGF-β 1 表达将全身性（在血浆中）或局部性（在血浆中）增加。 动脉壁）。在目标3中，TGF-β 1对动脉壁的作用将被证实。 通过破坏平滑肌细胞中的TGF-β 1信号传导来阻断。两个目标2 3、手法对动脉粥样硬化形成的影响 将被衡量。 这些实验将确定TGF-β 1对表型的影响， 正常和动脉粥样硬化动脉，阐明分子和细胞， 产生这些效应的机制，并阐明这些机制 通过其调节动脉壁中的TGF-β 1表达。的结果 这些调查将揭示， TGF-β 1对动脉壁的作用代表了有希望的方法， 预防和治疗动脉粥样硬化。

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.