MOLECULAR PHARMACOLOGY OF ADRENERGIC RECEPTORS IN AGING

该提案的目标是研究表达的调节 α和β肾上腺素能受体亚型与器官衰老， 心血管系统，有特别的关系， 老年患者的病理生理学和药物治疗。 一个 大量的工作表明， 随着增加， 年龄 令人兴奋的最新进展表明， 儿茶酚胺通过一系列肾上腺素能受体亚型介导， 比以前认识到的更加多样化。 之间的相互作用 这些新描述的受体亚型的器官特异性表达 以及随着年龄的增长可能发生的变化是发展的重要基础 针对老年人的新型药物疗法， 肾上腺素能激动剂或拮抗剂。 拟议工作的第一个目标是 研究α和β肾上腺素能受体的分布 使用分子生物学技术， 旨在定量受体mRNA并比较 这些mRNA在年龄范围内的变化。 表达 将测量以下基因：β 1和β 2; α 1A、α 1B和 α 1C;以及α 2A、α 2B和α 2C 组织中的儿茶酚胺 这些组织将包括：心脏、几种血液 血管;肝脏;前列腺和膀胱;肾脏;肺;和大脑（皮质和 小脑）。 这些研究将使用北方印迹法或定量免疫印迹法。 应用聚合酶链反应来测量特别罕见的 mRNA的。 这些研究的结果将与 用放射性配体结合测定受体蛋白量 技术或使用将制备的多克隆兔抗体 针对不同肾上腺素能受体亚型的特异性肽。 该提案的第二个主要目标是调查 这些受体基因的调节受到以下因素的不同修饰 几个重要的病理生理状态在年轻与老年大鼠。 在 一般来说，随着年龄的增长，生物体的能力下降， 对由疾病或药物引起的病理生理扰动作出反应。 过量甲状腺激素对这些基因表达的影响， 将检查年轻和年老动物的心脏和大脑。 还 三环类抗抑郁药对基因表达的调节作用 年轻和年老的老鼠大脑中的蛋白质会被比较。

The goals of the proposal are to investigate the regulation of expression of alpha and beta adrenergic receptor subtypes with aging in organs such as the cardiovascular system that have particular relevance to the pathophysiology and pharmacologic treatment of geriatric patients. An extensive body of work has demonstrated that there are important alterations in the physiological effects of catecholamines with increasing age. Exciting recent advances have demonstrated that the effects of catecholamines are mediated via a range of adrenergic receptor subtypes far more diverse than had previously been appreciated. The interplay between the organ-specific expression of these newly described receptor subtypes and possible changes with aging is an important basis for the development of novel drug therapies for the elderly using highly subtype specific adrenergic agonists or antagonists. The first goal of the proposed work is to investigate the distribution of alpha and beta adrenergic receptor subtypes in a number of important organs using molecular biological techniques aimed at quantifying receptor mRNA's and comparing the abundance of these mRNA's across the age range in Fischer 344 rats. Expression of the following genes will be measured: beta1 and beta2; alpha1A, alpha1B and alpha1C; and alpha2A, alpha2B, and alpha2C in a number of important target tissues for catecholamines. The tissues will include: heart, several blood vessels; liver; prostate and bladder; kidney; lung; and brain (cortex and cerebellum). These studies will use Northern blotting or a quantitative application of the polymerase chain reaction to measure particularly rare mRNA's. Results of these studies will be compared with determinations of the amount of receptor protein, assayed either with radioligand binding techniques or with polyclonal rabbit antibodies that will be prepared against peptides specific for the different adrenergic receptor subtypes. The second major goal of the proposal is to investigate the possibility that regulation of these receptor genes is differentially modified by several important pathophysiological states in young versus old rats. In general, with aging there is a decline in the capacity of an organism to respond to pathophysiological perturbations induced by disease or drugs. The effects of excess thyroid hormone on the expression of these genes in the heart and brain of young and old animals will be examined. Also, the effects of a tricyclic antidepressant on the regulation of gene expression in the brains of young and old rats will be compared.