HUMAN ANGIOTENSIN II RECEPTOR GENE REGULATION

描述：高血压，一个主要的公共卫生问题，困扰着更多 占总人口的15%以上，是 心血管疾病和心力衰竭、肾衰竭和 卒中。由于肾素-血管紧张素系统(RAS)在 盐和水的动态平衡和血管张力的维持 这一系统的组成部分代表了一种潜在的可能的病因。 高血压。该提案将重点关注血管紧张素II(Ang II) 受体，RAS的一个组成部分，因为这些细胞表面受体是 负责调节血管紧张素Ⅱ的生理效应。最近，它是 证明血管紧张素11与两个药理上不同的 血管紧张素Ⅱ受体亚型AT1和AT2。的完整刻画 AT1和AT2受体的结构和生化特性 他们的基因对于全面理解调控是必不可少的 血管紧张素Ⅱ的作用及其受体在血管紧张素转换酶中的潜在作用 高血压和其他心血管疾病的发病机制。 目前，对人类AT1和AT2受体(HAT1R)知之甚少 和hAT2R)基因或它们是如何转录调控的，以及为什么 合成了多个选择性剪接的mRNA转录本。 此外，对其功能或信号转导知之甚少。 机制(S)的hAT2R。因此，这个项目的长期目标是 是对hAT1R和hAT2R基因的特征，并研究hAT1R和hAT2R基因 调节这些基因表达的分子机制 鉴定hAT2R的生化性质。 这项建议的具体目的是：1)定义顺式监管 选择性指导hAT1R转录的机制 和hAT2R基因，利用DNA介导的基因转移，2)检测 假设四个不同的hAT1R mRNAs有差异表达， 3)测试四个不同的hAT1R mRNA转录本是 体外和体内翻译效率不同，4)测试 假设含有外显子3的hAT1R mRNAs编码一个新的hAT1R，和5) 利用酵母双杂交系统研究hAT2R信号转导 机制(S)。

DESCRIPTION: Hypertension, a major public health problem afflicting more than 15% of the population, is the most significant risk factor in cardiovascular disease and major cause of heart failure, kidney failure and stroke. Since the renin-angiotensin system (RAS) plays a central role in salt and water homeostasis and the maintenance of vascular tone, each component of this system represents a potential candidate in the etiology of hypertension. This proposal will focus on the angiotensin II (Ang II) receptor, a component of the RAS, since these cell-surface receptors are responsible for mediating Ang II physiological effects. Recently, it was demonstrated that Ang 11 interacts with two pharmacologically distinct subtypes of Ang II receptors, AT1 and AT2. The complete characterization of the structural and biochemical properties of the AT1 and AT2 receptors and their genes is essential for the full understanding of the regulatory actions of Ang II and the potential role of these receptors in the pathogenesis of hypertension as well as other cardiovascular disorders. Currently, very little is known about the human AT1 and AT2 receptors (hAT1R and hAT2R) genes or how they are transcriptionally regulated and why multiple alternatively spliced mRNA transcripts are synthesized. Furthermore, little is known about the function or the signal transduction mechanism(s) of the hAT2R. Therefore, the long term goals of this project are to characterize the hAT1R and hAT2R genes and to investigate the molecular mechanisms that regulate the expression of these genes and to characterize the biochemical properties of the hAT2R. The specific aims of this proposal are to: 1) Define the cis-regulatory mechanisms involved in selectively directing the transcription of the hAT1R and hAT2R genes by utilizing DNA-mediated gene transfer, 2) Test the hypothesis that the four distinct hAT1R mRNAs are differentially expressed, 3) Test the hypothesis that the four distinct hAT1R mRNA transcripts are translated with differential efficiencies in vitro and in vivo, 4) Test the hypothesis that hAT1R mRNAs which harbor exon 3 encode a novel hAT1R, and 5) Utilize the yeast two-hybrid system to investigate hAT2R signal transduction mechanism(s).