PPAR-Mediated Inhibition of Vascular Remodeling

描述（由申请人提供）：PPAR？过氧化物酶体增殖激活受体（peroxisome proliferator-activated receptor）是一种配体激活的转录因子，调节葡萄糖和脂质代谢。激活PPAR的药物？显著改善糖尿病患者的代谢谱，从而改善其心血管功能。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？在免疫机制中参与动脉粥样硬化和血管重构的发病机制尚未得到解决。我们在人源化小鼠模型中检测了两种PPAR3配体15-脱氧前列腺素- j2 （15-d- pgj2）和西格列酮对体内T细胞诱导的人动脉重构的影响。PPAR吗?配体阻止重塑，这种保护作用被PPAR？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血管炎症，我们研究了PPAR？在这些初级人类细胞中。最显著的是PPAR？在T细胞亚群中，在活化调节性T细胞中观察到最高的表达。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？配体都有PPAR吗？依赖，以及独立的作用，我们建议结合分子和药理学方法来剖析PPAR？在体外和体内，人类EC和T细胞之间的相互作用。我们假设PPAR的抑制作用？动脉重塑的激活可能通过激活调节性T细胞和维持EC静止来介导。该项目的具体目标是：第一，确定PPAR的作用？用同种异体反应性PBMC和/或CD34祖细胞重建后移植到SCID小鼠体内的人动脉段的重塑；二是确立PPAR的职能角色。通过基因修饰PPAR水平对人EC和T细胞亚群的影响体外表达及功能检测；最后，剖析PPAR的作用？通过改变其在T细胞、EC细胞或两者中的表达水平。在最后一个目标中，我们将采用我们的模型，利用新生形成的血管床，这使我们能够在微血管网络形成之前对EC进行遗传修饰。了解这些细胞机制将对与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描述人内皮细胞和白细胞之间的相互作用和免疫激活。这些机制的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.