PPAR-Mediated Inhibition of Vascular Remodeling

描述(由申请人提供)：PPAR？过氧化物酶体增殖物激活受体是一种配体激活的转录因子，调节糖脂代谢。激活PPAR的药物？显著改善糖尿病患者的代谢状况，从而改善他们的心血管功能。最近，人们认识到PPAR？配体在几种小鼠模型中抑制炎症性疾病。然而，PPAR的作用是什么？在免疫机制方面，参与动脉粥样硬化和血管重塑的发病机制尚未得到解决。我们在我们的人源化小鼠模型中测试了两种PPAR3配体15-d-前列腺素J2(15-d-PGJ2)和西格列酮对T细胞诱导的人动脉重塑的体内作用。PPAR？配体可以阻止重塑，而这种保护通过与PPAR同时处理而被取消？拮抗剂，GW9662。由于内皮细胞(EC)和淋巴细胞之间的相互作用引发了血管炎症，我们研究了PPAR？在这些原代人类细胞中。最值得注意的是PPAR的表达差异？在T细胞亚群中，观察到在激活的调节性T细胞中表达最高。这表明PPAR？配体可能通过激活调节性T细胞的抑制功能来抑制炎症反应。考虑到PPAR？配体有两种PPAR吗？依赖和独立的作用，我们建议结合分子和药理学方法来剖析PPAR？在体外和体内人EC和T细胞的相互作用中。我们假设PPAR？激活动脉重塑可能通过激活调节性T细胞和维持EC静止来实现。这个项目的具体目标是：第一，确定PPAR的作用？在同种异体反应性PBMC和/或CD34祖细胞重建后移植到SCID小鼠体内的人动脉节段的重塑；第二，建立PPAR？在人类EC和T细胞亚群中，通过遗传改变PPAR的水平？并在体外表达并检测它们的功能；最后，剖析PPAR？在体内，通过改变其在T细胞、EC或两者中的表达水平。在最后一个目标中，我们将使用我们的模型，利用新生形成的血管床，允许我们对EC先前形成的微血管网络进行遗传修饰。了解这些细胞机制将对动脉粥样硬化和移植物动脉硬化相关的血管炎症的治疗产生重大影响。公共卫生相关性：该项目将确定转录因子PPAR的作用？(过氧化物酶体增殖物激活受体)转录因子在动脉粥样硬化等血管疾病模型中的作用。研究将在一种新的人源化小鼠模型中表征人内皮细胞和白细胞之间的相互作用和免疫激活。这些机制研究将对血管疾病的治疗具有重要意义。

DESCRIPTION (provided by applicant): PPAR? (peroxisome proliferator-activated receptor) is a ligand-activated transcription factor that regulates glucose and lipid metabolism. Drugs activating PPAR? significantly improve metabolic profiles in diabetic patients, and consequently also their cardiovascular function. More recently, it was recognized that PPAR? ligands inhibit inflammatory diseases in several mouse models. However, the role of PPAR? in immune mechanisms involved in the pathogenesis of atherosclerosis and vascular remodeling has not been addressed. We tested the in vivo effects of two PPAR3 ligands, 15 deoxy-prostaglandin-J2 (15-d-PGJ2) and ciglitazone, on T cell induced remodeling of human artery in vivo in our humanized mouse model. PPAR? ligands prevented remodeling, and this protection was abrogated by simultaneous treatment with the PPAR? antagonist, GW9662. Since the interactions between endothelial cells (EC) and lymphocytes initiate vascular inflammation, we investigated the expression of PPAR? in these primary human cells. Most remarkable were the differences in expression of PPAR? in T cell subpopulations, where the highest expression was observed in activated regulatory T cells. This suggests that PPAR? ligands may inhibit inflammatory responses via activating suppressive functions of regulatory T cells. Given that PPAR? ligands have both PPAR? dependent, as well as independent effects, we propose to combine molecular and pharmacological approaches to dissect the role of PPAR? in the interactions between human EC and T cells both in vitro and in vivo. We hypothesize that the inhibitory effects of PPAR? activation on arterial remodeling may be mediated via activating regulatory T cells and via maintaining EC quiescent. The specific aims of this project are: first, to determine the role of PPAR? in remodeling of human artery segments grafted into SCID mice after reconstitution with alloreactive PBMC and/or CD34 progenitors; second, to establish the functional roles of PPAR? in human EC and T cell subsets by genetically modifying the levels of PPAR? expression and testing their function in vitro; and finally, to dissect the role of PPAR? in vivo by altering its expression level in T cells, EC or both. In the last aim, we will employ our model utilizing a de novo formed vascular bed which allows us to genetically modify EC prior formation of microvascular network. Understanding these cellular mechanisms will have significant impact on treatment of vascular inflammation that is associated with atherosclerosis and graft arteriosclerosis. PUBLIC HEALTH RELEVANCE: This project will determine the role of the transcription factor PPAR? (peroxisome proliferator-activated receptor) transcription factor in a model of vascular diseases such as atherosclerosis. Studies will characterize the interactions and immune activation occurring between human endothelial cells and leukocytes in a novel humanized mouse model. These mechanistic studies will have significant implications for treatment of vascular diseases.