PHARMACOLOGY OF VASCULAR AL-ADRENERGIC RECEPTORS

血管α-肾上腺素能受体的药理学

• 批准号: 6795941
• 负责人: Debra Anne Schwinn
• 金额: $ 40.86万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-29 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6795941
• 关键词: DNA footprinting; RNase protection assay; alpha adrenergic receptor; biological signal transduction; blood vessels; cardiovascular pharmacology; gel mobility shift assay; gene mutation; genetic polymorphism; genetic regulatory element; human tissue; hypertension; myocardial ischemia /hypoxia; protein structure function; receptor expression; tissue /cell culture; transcription factor

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.

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 健康和疾病中的血管肾上腺素受体（AR）。在此背景下， 该提案通过检查潜在机制来关注人类 alpha1-AR 常氧和缺氧条件下血管特异性 α1-AR 亚型表达 作为与高血压相关的基因组 α1a-AR 突变的检查。 α1-AR药理学的一个独特方面是α1-AR的表达和功能 血管 α1-AR 取决于所研究的物种和所检查的血管床。在 与大鼠和小鼠相反，其中 A1b 和 alpha1d-AR 占主导地位并介导 许多血管收缩，研究人员实验室的最新数据 表明 alpha1a-AR 在几乎所有人类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 RNA 和蛋白质水平的表达外，他们还证实 α1a-AR 介导人体血管收缩。他们现在建议审查 人类α1-AR亚型血管特异性表达的机制 检验人类血管α1-AR表达差异的假设 (alpha1>alpha1d) 由血管特异性 5'-调节组合产生 序列和组织特异性转录因子；选择 alpha1d 是为了 这种比较是因为它在许多含有 alpha1aAR 的人类血管中不存在 表示。研究人员最近克隆并鉴定了 6.2kb 5'UTR [0122] 人类α1-AR基因(Razik等人，J Biol Chem，1997；272：28237-28246)； 因此，他们处于独特的地位，可以在以下两个方面检验这一假设： 常氧和缺氧。由于 alpha1a-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具体 遗传多态性导致 alpha1-AR 血管表达增强和/或 与高血压相关的组成性活动。对此，他们 已经确定了人类 8 号染色体区域之间的连锁 α1-AR 驻留和收缩压。另外，他们最近 在试点研究中鉴定出 1.3kb alpha1-AR 编码区的 3 个多态性 来自 5 个人。额外的多态性将从 192 开始测序 个体来识别临床相关的多态性）。他们提议 测试这些多态性在组织培养中的功能意义 将每个多态性与血管相关联。

项目成果

Modulation of bladder alpha1-adrenergic receptor subtype expression by bladder outlet obstruction.

• 发表时间: 2002
• 期刊: The Journal of urology
• 作者: C. Hampel;P. C. Dolber;Michael P. Smith;S. Savic;Joachim W Th roff;K. Thor;D. Schwinn

alpha1-Adrenoceptor subtype selectivity and lower urinary tract symptoms.

α1-肾上腺素受体亚型选择性和下尿路症状。

• DOI: 10.4065/79.11.1423
• 发表时间: 2004
• 期刊: Mayo Clinic proceedings
• 影响因子: 8.9
• 作者: Schwinn,DebraA;Price,DavidT;Narayan,Perinchery
• 通讯作者: Narayan,Perinchery