Metabolic responsive factors in cardiovascular disease

描述(申请人提供)：PPAR-y是抗糖尿病药物噻唑烷二酮(TZDS)的主要靶点，是一种转录因子，它占据着整合代谢和心血管反应的位置。PPAR-y对脂肪形成至关重要，PPAR-y的突变已被证明会导致胰岛素抵抗、糖尿病和高血压。TZD最近被证明可以改变动物和人类的血压，并改变血管内皮细胞和血管平滑肌功能。因此，PPAR-y可能是调节代谢性疾病和心血管疾病之间的界面的候选基因。然而，目前尚不清楚血管组织中的PPAR-y是否对体内反应起关键作用，以及TZD对血管功能的影响是否通过PPAR-y介导。我们的目标是确定PPAR-y在心脏和血管细胞中的作用，并确定其在调节代谢和心血管疾病之间的关系中的作用。这项提案将回答三个关键问题。在其他正常动物中，PPAR-y在心血管系统中的生理功能是什么？PPAR-y在病理疾病模型中的作用是什么？最后，PPAR-y和TZD效应的机制是什么(即PPAR-y介导的TZD效应以及分子机制是什么？)为了回答这些问题，我们创造了一种新的“全身”PPAR-y基因敲除，即心肌细胞和内皮细胞类型的限制性基因敲除，并提出了平滑肌细胞基因敲除。我们将使用多学科方法，重点研究这些基因敲除，以确定心血管PPAR-y的生理作用和作用机制。通过确定这些基因敲除动物的表型，我们预计将确定PPAR-y在心血管组织中的作用。因此，我们将能够确定PPAR-y是否介导TZD效应。根据我们的初步数据，我们将检验PPAR-y对心血管细胞生长的正常调节、保护细胞免受糖尿病血糖毒性和调节血压(可能主要在内皮细胞中)至关重要的假设--所有这些都是在生理学重要的背景下进行的。

DESCRIPTION (provided by applicant): PPAR-y, a major target for the antidiabetic thiazolidinediones (TZDs), is a transcription factor that occupies a position integrating metabolic and cardiovascular responses. PPAR-y is critical for adipogenesis and mutations in PPAR-y have been shown to cause insulin resistance, diabetes and hypertension. TZDs have recently been shown to alter blood pressure in animals and humans and to modify vascular endothelial and smooth muscle function. Therefore, PPAR-y is likely candidate for mediating the interface between metabolic disease and cardiovascular disease. However, it is unclear if PPAR-y in vascular tissues is critical to in vivo responses and whether TZD effects on vascular function are mediated by PPAR-y. Our goal is to determine the role of PPAR-y in cardiac and vascular cells and to determine its role in mediating the associations of metabolic and cardiovascular diseases. This proposal will answer three critical questions. What is the physiologic function of PPAR-y in the cardiovascular system in otherwise normal animals? What is the role of PPAR-y in pathologic disease models? Finally, what are the mechanisms of PPAR-y and TZD effects (i.e. what TZD effects mediated by PPAR-y and what are the molecular mechanisms?)? To answer these questions, we have produced a novel "whole body" PPAR-y knockout, cardiomyocyte and endothelial cell-type restricted knockouts and propose smooth muscle cell knockouts. We will use a multidisciplinary approach, focused on these gene knockouts, to determine the physiologic role and mechanisms of action of the cardiovascular PPAR-y. By determining the phenotype of these knockout animals we anticipate defining the role of PPAR-y in cardiovascular tissue. Therefore, we will be able to determine if PPAR-y mediates TZD effects. Based on our preliminary data, we will test the hypothesis that PPAR-y is critical to normal regulation of cardiovascular cell growth, protects cells from diabetic glucolipotoxicity and regulates blood pressure (likely predominately in the endothelial cell)-All in a physiologic important context..