PHARMACOLOGY OF VASCULAR AL-ADRENERGIC RECEPTORS

这项研究的总体长期目标是了解 人的调节、表达和功能之间的动态相互作用 血管肾上腺素能受体(ARs)与健康和疾病在此背景下， 这项建议通过研究潜在的机制来关注人类α-ARs。 血管特异性α1-AR亚型在常氧和低氧中的表达 作为与高血压相关的基因组α1a-AR突变的检测。 α1-AR药理学的一个独特方面是它的表达和功能 维管束α-ARs取决于所研究的物种和检查的维管束床。在……里面 与大鼠和小鼠形成对比，在大鼠和小鼠中，A1b和Alpha1d-Ars占主导地位并起到调节作用 研究人员实验室的最新数据显示，许多血管收缩 表明α1a-Ars在几乎所有人的动脉中都占主导地位(例如 冠状动脉、肝脏、乳腺、肠系膜、肺、肾)和许多静脉床。 除了在RNA和蛋白质水平上表达外，他们还证实了 α1a-Ars介导人体血管收缩。他们现在提议检查 人α1-AR亚型血管特异性表达的机制 检验人类血管α1-AR差异表达的假说 (alpha1&gt；alpha1d)是血管特异性5‘-调节因子组合的结果 序列和组织特定的转录因子；字母1d被选择用于 这种比较是因为在许多人的血管中不存在这种比较，而这些血管中存在α1受体 表达。研究人员最近克隆并鉴定了6.2kb的5‘非编码区 人类α1-AR基因(Razik等人生物化学杂志，1997年；272：28237-28246)； 因此，他们处于一个独特的位置来检验这一假说 常氧和低氧。由于α1a-Ars在人类内脏和 阻力动脉床，他们的第二个特定目标是检查是否特定 基因多态导致α1-AR血管表达增强和/或 与高血压相关的体质活动。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 α1-AR驻留和收缩压。此外，他们最近 初步研究中发现1.3kbα1-AR编码区的3个多态 来自5个人。更多的多态将从192个 个体识别临床相关的多态)。他们提议 测试这些多态在组织培养中的功能意义 每种多态都与血管相关。

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.