Metabolic responsive factors in cardiovascular disease

抗糖尿病药物噻唑烷二酮类（TZDs）的主要靶点是一种转录因子， 占据了整合代谢和心血管反应的位置。PPAR-y对脂肪形成至关重要 并且PPAR-y的突变已被证明会导致胰岛素抵抗、糖尿病和高血压。TZDs 最近已显示可改变动物和人类的血压， 和平滑肌功能。因此，PPAR-y可能是介导 代谢疾病和心血管疾病。然而，目前还不清楚血管组织中的PPAR-y是否是关键的， 体内反应以及TZD对血管功能的作用是否由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，并确定其在介导 代谢和心血管疾病的关联。 这项提议将回答三个关键问题。PPAR-y的生理功能是什么？ 心血管系统在其他方面正常的动物？PPAR-y在病理性疾病中的作用 模特？最后，PPAR-y和TZD效应的机制是什么（即TZD效应是由什么介导的？ PPAR-y和分子机制是什么？）为了回答这些问题，我们创作了一部小说 “全身”PPAR-y基因敲除、心肌细胞和内皮细胞型限制性敲除和建议 平滑肌细胞敲除。我们将使用多学科的方法，专注于这些基因敲除， 以确定心血管PPAR-y的生理作用和作用机制。通过确定 我们预期这些敲除动物的表型确定了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。根据初步数据，我们 PPAR-y对心血管细胞生长的正常调节至关重要， 细胞从糖尿病的糖脂毒性和调节血压（可能主要是在内皮细胞 细胞）-所有在生理重要的背景下。

PPAR^/, 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..