MOLECULAR PHARMACOLOGY OF ADRENERGIC RECEPTORS IN AGING

该提案的目的是调查表达的调节 α和β肾上腺素能受体亚型与衰老的关系 心血管系统与心血管系统特别相关 老年患者的病理生理和药物治疗。一个 广泛的工作表明，有重要的 儿茶酚胺的生理效应随剂量的增加而变化 年龄。令人振奋的最新进展表明， 儿茶酚胺是通过一系列肾上腺素能受体亚型介导的 比以前所欣赏的更加多样化。两者之间的相互作用 这些新描述的受体亚型的器官特异性表达 而可能的变化是随着年龄的增长而发展的重要基础 为老年人使用高度亚型特异性的新药物疗法 肾上腺素能激动剂或拮抗剂。拟议工作的第一个目标是 探讨肾上腺素能α、β受体的分布 用分子生物学方法研究几种重要器官的亚型 旨在量化受体mRNA和比较丰度的技术 在费舍尔344只大鼠中，这些信使核糖核酸的表达跨越了年龄范围。的表达 将测量以下基因：beta1和beta2；alpha1a、alpha1B和 Alpha1C；以及Alpha2A、Alpha2B和Alpha2C中的一些重要目标 儿茶酚胺的纸巾。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；和脑(皮质和 小脑)。这些研究将使用Northern印迹或定量 应用聚合酶链式反应检测特发性稀有物质 这些研究的结果将与测定的 用放射配基结合法检测受体蛋白的量 技术或将制备的多克隆兔抗体 针对不同肾上腺素能受体亚型特有的多肽。 该提案的第二个主要目标是调查 这些受体基因的调节是通过以下方式进行差异修改的 幼年大鼠与老年大鼠的几种重要的病理生理状态。在……里面 一般来说，随着年龄的增长，生物体的能力会下降 对疾病或药物引起的病理生理紊乱作出反应。 过量甲状腺激素对大鼠肺组织中这些基因表达的影响 将对幼年动物和老年动物的心脏和大脑进行检查。另外， 三环类抗抑郁药对基因表达调控的影响 在幼年和老年大鼠的大脑中进行比较。

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.