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传导的相关变化 系统. 如果已经确定了变化，目标将是 确定造成这些差异的机制。 第一组 与项目1合作进行的实验将测试两个 假设：首先，如果β 1-肾上腺素能受体 腺苷酸环化酶激活的影响 导致衰老相关的去甲肾上腺素能功能下降 （电生理反应和行为表现）和 一下 受体mRNA水平的降低是细胞凋亡的基础， 在这些受试者中，随着年龄的增长观察到特定的β-肾上腺素能受体亚型， 大脑区域。 许多神经递质受体，包括α 1- 肾上腺素能受体，使用肌醇1，4，5-三磷酸（IP 3）作为其第二个 使者 我们已经观察到IP 3促进Ca 2+的功效降低， 释放，仅限于老年大脑皮层。 第二组 的实验将测试的想法，这种老化相关的减少IP 3 有效性是由于IP 3受体的损失。 α 2-肾上腺素能亚型 受体最近已被确定，但很少有人知道有关 它们参与了中枢去甲肾上腺素能神经系统的衰老相关缺陷， 传输 第三组实验将使用定量的 放射自显影（QUAR），以确定α 2A和α 2B的变化。 大鼠大脑皮质、海马和中枢肾上腺素能受体 蓝斑（LC）作为衰老的函数。 我们还将研究功能 这些受体的变化与老化有关，通过测量调制， 这些受体诱发大脑皮层释放去甲肾上腺素， 不同年龄大鼠的海马切片。 第四套 该实验是与项目4合作进行的。 这些实验 将测量肾上腺素能受体亚型与QAR和相关的第二 在大鼠同种异体移植物（小脑， 海马和LC）。 几种不同的移植物和宿主年龄将 研究了 结果将提供证据，说明 衰老诱导的肾上腺素能神经元变化的内在或外在决定因素 受体，并应有助于确定机制（S）的潜在老化相关 功能变化。 在第五组实验中，我们提出，在 与项目6合作，以测试与衰老有关的假设， β肾上腺素能受体表达的差异仅限于 受神经支配的受体 β-肾上腺素能受体密度和β-肾上腺素能 受体刺激的环AMP产生将在 单核白细胞亚群和脂肪细胞分离自 年轻人和老年人健康志愿者 药物的潜在差异- 人脂肪细胞β-肾上腺素能受体的诱导调节 给予β-肾上腺素能受体拮抗剂噻吗洛尔 也可以作为年龄的函数。 综合来看， 拟议中的实验应该进一步了解什么时候 肾上腺素能受体和/或其与信号传导的偶联的改变 信号转导系统参与去甲肾上腺素能反应性的改变 这是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.