PHARMACOLOGY OF VASCULAR AL-ADRENERGIC RECEPTORS

这项研究的总体长期目标是了解 人类的调节、表达和功能之间的动态相互作用 血管肾上腺素能受体（AR）在健康和疾病中的作用。在这方面， 这项提案的重点是人类α 1-AR， 血管特异性α 1-AR亚型在常氧和缺氧中的表达，以及 作为与高血压相关的基因组alpha 1a-AR突变的检查。 α 1-AR药理学的一个独特方面是α 1-AR的表达和功能， 血管α 1-AR取决于研究的物种和检查的血管床。在 与大鼠和小鼠相反，在大鼠和小鼠中，A1 b和alpha 1d-AR占主导地位并介导 研究人员实验室的最新数据显示， 表明alpha 1a-ARs在几乎所有的人类动脉中占主导地位（例如， 冠状动脉、肝、乳腺、肠系膜、肺、肾）和许多静脉床。 除了在RNA和蛋白质水平上的表达，他们已经证实， α 1a-AR介导人血管收缩。他们现在建议检查 血管特异性表达人α 1-AR亚型的机制 检验人类血管α 1-AR表达差异 （α 1> α 1d）由血管特异性5 '-调节性 序列和组织特异性转录因子;选择alpha 1d用于 这种比较是因为它在许多人血管中不存在，在这些血管中， 表达。研究人员最近克隆并鉴定了6.2kb的5 'UTR， 人α 1-AR基因（Razik等，J Biol Chem，1997; 272：28237-28246）; 因此，他们处于一个独特的位置，以测试这一假设，在这两个 常氧和缺氧。由于α 1 α-AR在人类内脏和 阻力动脉床，他们的第二个具体目标是检查是否特异性 遗传多态性导致α 1-AR血管表达增强和/或 与高血压相关的固有活动。在这方面他们 已经确定了人类8号染色体区域之间的联系， α 1-AR驻留和收缩压。此外，他们最近 在初步研究中，在1.3kb α 1-AR编码区发现了3个多态性 从5个人。其他多态性将从192个 个体以鉴定临床相关的多态性）。他们提出 在组织培养中测试这些多态性的功能意义， 将每个多态性与血管相关。

The overall long-term objective of this research is to understand the dynamic interplay between regulation, expression, and function of human vascular adrenergic receptors (ARs) in health and disease. Within this context, this proposal focuses on human alpha1-ARs by examining mechanisms underlying vessel specific alpha1-AR subtype expression in normoxia and hypoxia, as well as examination of genomic alpha1a-AR mutations associated with hypertension. One unique aspect of alpha1-AR pharmacology is that expression and function of vascular alpha1-ARs depends on species studied and vascular bed examined. In contrast to rat and mouse, where A1b and alpha1d-ARs predominate and mediate contraction in many vessels, recent data from the investigators' laboratory demonstrates that alpha1a-ARs predominate in virtually all human arterial (e.g. coronary, hepatic, mammary, mesenteric, pulmonary, renal) and many venous beds. In addition to expression at RNA and protein levels, they have confirmed that alpha1a-ARs mediate human vessel contraction. They now propose examining mechanisms underlying vessel specific expression of human alpha1-AR subtypes by testing the hypothesis that differential human vascular alpha1-AR expression (alpha1>alpha1d) results from a combination of vessel specific 5'-regulatory sequences and tissue specific transcription factors; the alpha1d is chosen for this comparison since it is absent in many human vessels where alpha1aARs are expressed. The investigators recently cloned and characterized 6.2kb 5'UTR of the human alpha1-AR gene (Razik, et al. J Biol Chem, 1997; 272: 28237-28246); therefore they are in a unique position to test this hypothesis in both normoxia and hypoxia. Since alpha1a-ARs predominate in human splanchnic and resistance arterial beds, their second specific aim examines whether specific genetic polymorphisms result in enhanced alpha1-AR vascular expression and/or constitutively activity that correlates with hypertension. In this regard, they have identified a linkage between the region of human chromosome 8 where the alpha1-AR resides and systolic blood pressure. In addition, they recently identified 3 polymorphisms in 1.3kb alpha1-AR coding region in pilot studies from 5 individuals. Additional polymorphisms will be sequenced from 192 individuals to identify clinically relevant polymorphisms). They propose testing these polymorphisms for functional significance in tissue culture and correlating each polymorphism with vascular.