New Target For Stroke: Peroxisome Proliferator Activated Receptor-Gamma

描述（由申请人提供）：利用原代脑细胞培养和全动物系统建立过氧化物酶体增殖物激活受体（PPARy）促生存功能的机制，并对其在脑血管中的作用进行研究。在我们的初步研究中，我们证明了激活pparty(噻唑烷二酮（TZDs）和环戊酮前列腺素（CyPG）的治疗可以减少缺血性卒中和脑出血大鼠模型中的细胞死亡、炎症、梗死体积和行为功能障碍。吡格列酮（一种PPARy激动剂）在胰岛素抵抗患者中的临床多中心随机试验，旨在确定近期缺血性卒中患者致死性或非致死性卒中的风险，已启动有限的临床前背景。大约700万美国人每天服用tzd治疗胰岛素抵抗。由于胰岛素抵抗的人中风的风险很高，这些药物可能不仅对治疗急性中风有用，而且可以用来增强大脑对未来脑血管事件的抵抗力。本研究旨在研究氧糖剥夺细胞培养中PPARy的细胞基础，确定PPARy在基因改造小鼠缺血中的作用，并在一个成熟的大鼠中风模型中测试PPARy配体的药理作用。我们建议测试以下具体目标。1. 利用原代脑细胞培养，建立pparty促进生存功能的机制。2. 利用具有良好特征的局灶性缺血模型和基因工程小鼠，破坏1)神经元和2)小胶质细胞/巨噬细胞- PPAR， 3)过氧化氢酶（过氧化氢酶基因启动子含有功能性PPAR响应元件），以及4)转录因子核因子kappa-B （NF-KB； NF-KB被PPARy抑制），以建立PPARy抗缺血作用的机制。3. 评估pparty激动剂抗缺血活性的最佳条件（药物选择、剂量、有效治疗的时间窗口、耐受性和永久性与可逆性缺血的有效性）。

DESCRIPTION (provided by applicant): To establish, using primary brain cell cultures and whole animal system the mechanisms underlying pro- survival function of Peroxisome Proliferator Activated Receptor-y (PPARy) The cerebrovascular role of PPARy is understudied. In our preliminary studies we demonstrated that treatments that activate PPARy (thiazolidinediones (TZDs) and cyclopentanone prostaglandins (CyPG) reduce cell death, inflammation, infarct volume and behavioral dysfunction in rat models of ischemic stroke and intracerebral hemorrhage. A clinical multi-center randomized trial with pioglitazone (a PPARy agonist), in insulin resistant patients, aiming at determining risk for fatal or non-fatal stroke in patients with recent ischemic stroke, has been launched with limited pre-clinical background. Approximately 7 million Americans take TZDs daily for insulin resistance. Since people with insulin resistance are at high risk for stroke, these drugs may prove useful not only for management of the acute stroke, but may also be used to augment the brain's resistance to future cerebrovascular events. The present proposal seeks to investigate the cellular basis of PPARy in cell culture subjected to oxygen glucose deprivation, determine the role of PPARy in ischemia using genetically altered mice, and test the pharmacologic effects of PPARy ligands in a well-established in vivo rat stroke model. We propose to test the following specific aims. 1. To establish, using primary brain cell cultures, the mechanisms underlying pro-survival function of PPARy. 2. Utilizing a well-characterized focal ischemia model and genetically engineered mice with disrupted 1) neuronal-and 2) microglia/macrophage- PPARy, 3) catalase (catalase gene promoter contains a functional PPAR responsive element), and 4) the transcription factor, nuclear factor kappa-B (NF-KB; NF-KB is inhibited by PPARy), to establish mechanisms underlying the anti-ischemic role of PPARy. 3. To evaluate optimal conditions (selection of drug, dose, time window for effective treatment, tolerance, and effectiveness in permanent vs. reversible ischemia) for the anti-ischemic activity of PPARy agonists.