ADRENERGIC RECEPTORS DURING AGING

项目2的重点将继续是老龄化的调查- 肾上腺素能受体亚型及其信号转导的相关变化 系统。在已经确定更改的情况下，目标将是 确定造成这些差异的机制。第一套 与项目1合作进行的实验将测试两个 假设：首先，如果β1-肾上腺素能受体偶联发生变化 对大鼠小脑和海马腺苷环化酶激活的影响 与衰老相关的去甲肾上腺素能功能下降有关 (电生理反应和行为表现)和 第二。受体信使核糖核酸水平的降低是 随着年龄的增长观察到这些特定的β-肾上腺素能受体亚型 大脑区域。许多神经递质受体，包括α1- 肾上腺素能受体，使用肌醇1，4，5-三磷酸(IP3)作为第二受体 信使。我们观察到IP3促进钙离子的效果减弱。 释放，这仅限于老化的大脑皮层。第二盘 的实验将检验这种与衰老相关的IP3的下降 疗效是由于失去了IP3受体。α2-肾上腺素能亚型 最近发现了受体，但对此知之甚少。 它们参与了中枢去甲肾上腺素能与衰老相关的缺陷 变速箱。第三组实验将使用定量 放射自显影(QUAR)以确定α2a和α2b的变化- 大鼠大脑皮层、海马区和大脑部位的肾上腺素能受体 蓝斑(LC)是衰老的一种功能。我们还将调查功能 这些受体的变化与衰老有关，通过测量调制 这些诱发的去甲肾上腺素受体从大脑皮层和 取不同年龄大鼠的海马区脑片。第四套 实验是与项目4合作提出的。这些实验 将使用QAR和相关秒来测量肾上腺素能受体亚型 同种异体眼球移植中单侧和双侧的信使(小脑， 海马体和LC)。几种不同的移植物和寄主年龄将 学习。这一结果将提供证据证明 衰老引起肾上腺素能变化的内源性或外源性决定因素 受体和应有助于识别衰老相关的潜在机制(S) 功能变化。在第五组实验中，我们提出，在 与项目6合作，以测试与老龄化相关的假设 β=肾上腺素能受体表达的差异仅限于 神经感受器。β肾上腺素能受体密度与β肾上腺素能 受体刺激的环磷酸腺苷的生成将在 单核白细胞亚群和分离的脂肪细胞亚群 青年和老年健康志愿者。在药物方面的潜在差异- 诱导调节人脂肪细胞β-肾上腺素能受体的反应 使用β-肾上腺素能受体拮抗剂噻吗洛尔 也被确定为年龄的函数。总而言之，结果是 拟议中的实验应该会进一步加深我们对 肾上腺素能受体的变化和/或其与信号的偶联 信号转导系统参与去甲肾上腺素能反应性的改变 随着年龄的增长而发生的。

The focus of Project 2 will continue to be the investigation of aging- related changes in adrenergic receptor subtypes and their signaling systems. Where changes have already been identified, the goal will be to determine mechanisms responsible for these differences. The first set of experiments, carried out in collaboration with Project 1, will test two hypotheses: First that changes in coupling if beta1-adrenergic receptors to adenylate cyclase activation in rat cerebellum and hippocampus contribute to aging-related decreases in noradrenergic function (electrophysiological responsiveness and behavioral performance) and second. That reductions in receptor mRNA levels underlie the loss of specific beta-adrenergic receptor subtypes observed with aging in these brain regions. A number of neurotransmitter receptors, including alpha1- adrenergic receptors, use inositol 1,4,5-triphosphate (IP3) as their second messenger. We have observed a diminished efficacy of IP3 to promote Ca2+ release, which is restricted to the aged cerebral cortex. The second set of experiments will test the idea that this aging-related decrease in IP3 efficacy is due to a loss of IP3 receptors. Subtypes of alpha2-adrenergic receptors have recently been identified, but little is known concerning their involvement in aging-related deficits in central noradrenergic transmission. the third set of experiments will use quantitative autoradiography (QUAR) to identify changes in alpha2A and alpha2B- adrenergic receptors in rat cerebral cortex, hippocampus and locus coeruleus (LC) as a function of aging. We will also investigate functional changes in these receptors related to aging by measuring modulation by these receptors of evoked norepinephrine release from cerebral cortical and hippocampal slices from rats of different ages. The fourth set of experiments is proposed in collaboration with Project 4. these experiments will measure adrenergic receptor subtypes with QAR and related second messengers in single and double in oculo rat allograft (cerebellum, hippocampus and LC). Several different grafts and host ages will be studied. The results will provide evidence as to the importance of intrinsic or extrinsic determinants in aging-induced changes in adrenergic receptors and should help identify mechanism(s) underlying aging-related functional changes. In the fifth set of experiments, we proposed, in collaboration with Project 6, to test the hypotheses that aging-related differences in expression of beta=adrenergic receptors are limited to innervated receptors. beta-adrenergic receptor density and beta-adrenergic receptor-stimulated cyclic AMP generation will be compared in subpopulations of mononuclear leukocytes and in adipocytes isolated from young and elderly healthy volunteers. Potential differences in drug- induced regulation of human adipocyte beta-adrenergic receptors in response to administration of the beta-adrenergic receptor antagonist timolol will also be determined as a function of age. Taken together, the results of the proposed experiments should further our understanding of when alterations in adrenergic receptors and/or their coupling to signal transduction system contribute to changes in noradrenergic responsiveness that occur with aging.