ALPHA-2 ADRENERGIC RECEPTOR GENE TRANSCRIPTION

α 2肾上腺素能受体已被证明发挥重要作用 在肾功能的体内平衡和中枢神经系统的调节中， 交感神经系统 这些受体的功能障碍可能与 在发展和/或维持某些形式的高血压。 最近的分子分析表明，有三种亚型的 α 2肾上腺素能受体，每一个都由一个单独的基因编码， 人类 本项目的长期目标是了解相对 每种亚型对心血管功能和血液的贡献 压力调节 已经表明，这些受体中的每一种 亚型具有不同的组织特异性表达模式。 是 我们假设α 2肾上腺素能受体基因的多样性 允许基因的组织特异性表达， 转录调控和不同的生理反应， 刺激。 这项资助的目标是了解 各种α 2基因的组织特异性表达，并开始 分析细胞内和细胞外信号， 2基因表达。 具体目标如下：（1） 来研究这三个人的转录本的分布情况， α 2基因在脑和肾亚区的表达;（2）研究α 2基因在脑和肾亚区的顺式表达 各种α 2基因的调节区域， 通过比较假定的表达能力， 在一些实施方案中，转录调控区用于指导多种细胞系中的转录。 (3)表征重要的或组织特异性的核因子 通过分析α 2肾上腺素能受体基因的表达 DNA酶I足迹和凝胶迁移率中DNA/核因子相互作用的研究 转移分析，通过评估点突变的影响， 因子结合位点来改变转录， 关键核因子的分布。 (4)为了研究细胞内和 通过监测细胞外信号改变α 2基因转录 药物如cAMP或受体激动剂改变 在各种细胞系中转录，并研究顺式调节 通过方法调节这些影响的元素和反式作用因子 具体目标2和3。 这些研究将导致静脉注射的发展， 特异性地影响每个α 2基因的表达水平， 转录水平。 总之，拟议的研究将提供 关于基因表达和调控的重要信息 编码具有许多重要生物学功能的受体。

Alpha 2 adrenergic receptors have been shown to play an important role in homeostasis of kidney function and in the regulation of the central sympathetic system. Dysfunction of these receptors is probably involved in the development and/or maintenance of some forms of hypertension. Recent molecular analysis has shown that there are three subtypes of alpha 2 adrenergic receptors, each encoded by a separate gene in rat and human. The long term goal of this project is to understand the relative contributions of each subtype to cardiovascular function and blood pressure regulation. It has been shown that each of these receptor subtypes has a different pattern of tissue specific expression. It is our hypothesis that the diversity of alpha 2 adrenergic receptor genes allows for the tissue specific expression of genes that differ in their transcriptional regulation and vary in their response to physiological stimuli. It is the goal of this grant to understand the mechanism of tissue specific expression of various alpha 2 genes and to begin to analyze the intracellular and extracellular signals that regulate alpha 2 gene expression. The following specific aims will be undertaken: (1) to study the distribution of transcripts specific for each of the three alpha 2 genes in subregions of brain and kidney; (2) To study the cis regulatory regions of the various alpha 2 genes that may be responsible for their differential expression by comparing the ability of putative regulatory regions to direct transcription in a variety of cell lines. (3) To characterize nuclear factors that are important or tissue specific expression of a alpha 2 adrenergic receptor genes by analyzing DNA/nuclear factor interactions in DNase I footprinting and gel mobility shift assays, by assessing the effects of point mutations in nuclear factor binding sites to alter transcription and by studying the tissue distribution of key nuclear factors. (4) To study intracellular and extracellular signals that alter alpha 2 gene transcription by monitoring the ability of agents, such as cAMP or receptor agonists, to alter transcription in various cells lines and to study the cis regulatory elements and trans-acting factors that mediate these affects by methods in specific aims 2 and 3. These studies will lead to the development of intraventions to specifically affect the level of expression of each alpha 2 gene at the level of transcription. In summary, the proposed studies will provide important information concerning the expression and regulation of genes that encode the receptors that have many important biological functions.