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（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。药物激活过氧化物酶体增殖体激活受体？显著改善糖尿病患者的代谢特征，并因此改善其心血管功能。最近，人们认识到，PPAR？配体在几种小鼠模型中抑制炎性疾病。但是，PPAR的作用？在免疫机制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PPAR 3配体15-d-PGJ 2和ciglitazone对T细胞诱导的体内人动脉重塑的体内作用。PPAR？配体防止重塑，这种保护被废除的同时治疗与过氧化物酶体增殖物激活受体？拮抗剂GW 9662。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，我们调查的表达？在这些原始人类细胞中。最显着的差异表达的过氧化物酶体增殖物激活受体？在T细胞亚群中，在活化的调节性T细胞中观察到最高表达。这表明，PPAR？配体可以通过激活调节性T细胞的抑制功能来抑制炎症反应。鉴于此，PPAR？配体既有过氧化物酶体增殖物激活受体？依赖的，以及独立的影响，我们建议联合收割机分子和药理学的方法来解剖的作用，过氧化物酶体增殖物激活受体？在体外和体内人类EC和T细胞之间的相互作用。我们推测，抑制作用的过氧化物酶体增殖物激活受体？对动脉重塑的激活可以通过激活调节性T细胞和通过维持EC静止来介导。该项目的具体目标是：第一，以确定的作用？重建移植到SCID小鼠的人动脉段后，同种异体反应性PBMC和/或CD 34祖细胞重建;第二，建立的功能作用的过氧化物酶体增殖物激活受体？在人类EC和T细胞亚群的基因修饰水平的过氧化物酶体增殖物激活受体？表达和测试他们的功能在体外;最后，解剖的作用？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，我们将采用我们的模型，利用从头形成的血管床，使我们能够遗传修饰EC之前形成的微血管网络。了解这些细胞机制将对治疗与动脉粥样硬化和移植物动脉硬化相关的血管炎症产生重大影响。公共卫生相关性：该项目将确定转录因子PPAR的作用？在血管疾病如动脉粥样硬化的模型中的过氧化物酶体增殖物激活受体（peroxisome proliferator-activated receptor）转录因子。研究将描述在新型人源化小鼠模型中人内皮细胞和白细胞之间发生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.