DRUGS AND DEVELOPMENT OF THE ADRENERGIC NERVOUS SYSTEM

最终目标是确定潜在的细胞机制。 细胞发育的神经递质控制和相应的药物- 诱发功能性畸形学。我们已经确定了两个潜在的测试版- 控制细胞发育的肾上腺素能机制：对 细胞复制和分化的时间，以及 细胞内信使系统。具体目标是： (L)明确脑发育对神经元输入的要求 β肾上腺素能受体介导的影响分化的反应 去甲肾上腺素能靶细胞。这将通过新生儿化学物质进行评估 用6-羟基多巴胺去神经。 (2)确定β-受体脱敏在脑缺血再灌注损伤中的作用 发育过程；受体脱敏的几个方面不能 由新生儿服用激动剂引起，并且只出现在 突触前神经元功能的开始和成熟期的激增 神经冲动活动。这将通过挑战动物来评估 反复注射异丙肾上腺素，开始于不同的阶段 发展。 (3)评价围产期甲状腺激素的允许作用。 在发育期建立β受体介导的反应 在神经元活动成熟激增之前。 对于每个特定的目标，我们将评估β-受体的发展。 结合位点数、亲和力状态和亲和力位移与G- 蛋白质功能)，以及与腺苷环化酶的受体通过 G-S将与阿尔法-2受体进行比较，后者是暂时的 在发育中的组织中过度表达，并与alpha2链接到 通过G-I抑制腺苷环化酶。 与神经递质相关的受体刺激终点 细胞分化的控制将使用每种模型进行评估： 受体介导的DNA合成终止；刺激 发育表达的原癌基因c-fos及其功能 AP-L结合络合物形成的终点和形成的时间 突触后分化，通过肾上腺素能神经元的转换来评估 受体亚型、肌球蛋白亚型转换和RNA/DNA比率。 心脏和肝脏这两个组织将被研究，因为它们的不同 发育模式：心脏中的β-受体及其与 腺苷环化酶存在于发育的早期，并随着 发育；在肝脏中，有一种发育的β- 受体及其刺激腺苷环化酶的能力。这些研究 因此应该确定神经元和荷尔蒙输入在 β-肾上腺素能信号主要成分的研究进展 级联反应，并通过肾上腺素能调控靶细胞分化 神经元输入；对比具有不同模式的两个组织 受体个体发育应该使我们能够确定这些角色是否 通用的，或者更确切地说，是特定于选择性靶组织的。

The ultimate goals are to identify the cellular mechanisms underlying neurotransmitter control of cell development and corresponding drug- induced functional teratology. We have identified two potential beta- adrenergic mechanisms for control of cell development: effects on the timing of cell replication and differentiation, and "programming" of intracellular messenger systems. The specific aims are: (l) Identify the requirement for neuronal input in the development of beta-adrenergic receptor mediated responses that influence differentiation of noradrenergic target cells. This will be evaluated by neonatal chemical denervation with 6-hydroxydopamine. (2) Identify the role of beta-receptor desensitization in the developmental process; several aspects of receptor desensitization cannot be elicited by agonist administration in the neonate, and appear only with the onset of presynaptic neuronal function and a maturational surge in neuronal impulse activity. This will be evaluated by challenging animals with repeated injections of isoproterenol, begun at different stages of development. (3) Evaluate the permissive role of perinatal thyroid hormones in establishing beta-receptor-mediated responses in the developmental period preceding the maturational surge of neuronal activity. For each specific aim, we will assess the development of beta-receptor binding sites (numbers, affinity state, and affinity shift linked to G- protein function), as well as the receptor link to adenylate cyclase via G-S. Comparisons will be made with alpha2-receptors, which are transiently overexpressed in developing tissues, and with the alpha2-link to inhibition of adenylate cyclase via G-i. Endpoints of receptor stimulation that are relevant to neurotransmitter control of cell differentiation will be evaluated with each model: receptor-mediated termination of DNA synthesis; stimulation of the developmentally-expressed protooncogene, c-fos; and its functional endpoint of formation of AP- l binding complexes; and the timing of postsynaptic differentiation, evaluated by switchovers of adrenergic receptor subtypes, myosin isoform transitions and RNA/DNA ratios. Two tissues, heart and liver, will be studied because of their different developmental patterns: in the heart beta-receptors and their linkage to adenylate cyclase are present early in development and increase with development; in the liver, there is a developmental decline in beta- receptors and their ability to stimulate adenylate cyclase. These studies should thus identify the role of neuronal and hormonal input in the development of the major components of the beta-adrenergic signaling cascade, and in the control of target cell differentiation by adrenergic neuronal input; contrasting two tissues that have disparate patterns of receptor ontogeny should enable us to determine if these roles are universal or rather are specified to selective target tissues.