DRUGS AND DEVELOPMENT OF THE ADRENERGIC NERVOUS SYSTEM

药物和肾上腺素能神经系统的发育

• 批准号: 2196686
• 负责人: THEODORE A SLOTKIN
• 金额: $ 19.55万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1976
• 资助国家: 美国
• 起止时间: 1976-06-15 至 1999-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2196686
• 关键词: 6 hydroxydopamine; G protein; adenylate cyclase; beta adrenergic receptor; denervation; developmental neurobiology; drug tolerance; heart; heart pharmacology; histocompatibility antigens; hormone regulation /control mechanism; hyperthyroidism; hypothyroidism; isoproterenol; laboratory rat; liver; liver pharmacology; neurogenesis; neuropharmacology; newborn animals; norepinephrine; receptor binding; receptor coupling; receptor expression; thyroid hormones

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.

最终的目标是确定潜在的细胞机制 神经递质控制细胞发育和相应的药物- 诱发功能畸形学我们发现了两个潜在的β- 控制细胞发育的肾上腺素能机制：对细胞的影响 细胞复制和分化的时机，以及细胞的"编程"， 细胞内信使系统具体目标是： (l)确定神经元输入的发展需要， 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评估 6-羟基多巴胺去神经。 (2)确定β-受体脱敏在 发育过程;受体脱敏的几个方面不能 在新生儿中通过激动剂给药引起，并且仅在 突触前神经元功能的开始和 神经冲动活动这将通过挑战动物进行评价 在不同的阶段开始反复注射异丙肾上腺素， 发展 (3)评价围产期甲状腺激素在妊娠中的容许作用 在发育期建立β受体介导的反应 在神经元活动成熟之前。 对于每一个特定的目标，我们将评估β受体的发展， 结合位点（数量、亲和力状态和与G- 蛋白质功能），以及受体连接到腺苷酸环化酶通过 G-S将与α 2受体进行比较，α 2受体是瞬时的， 在发育中的组织中过度表达，并与α 2-连接， 通过G-i抑制腺苷酸环化酶。 与神经递质相关的受体刺激终点 将使用每种模型评价细胞分化的控制： 受体介导的DNA合成终止; 原癌基因c-fos及其功能 AP-1结合复合物形成的终点; 突触后分化，通过肾上腺素能神经元的转换来评价。 受体亚型、肌球蛋白亚型转换和RNA/DNA比率。 两种组织，心脏和肝脏，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 腺苷酸环化酶存在于发育早期， 发育;在肝脏中，β- 受体及其刺激腺苷酸环化酶的能力。这些研究 因此，应该确定神经元和激素输入的作用， β-肾上腺素能信号传导的主要成分的发展 级联反应，并在靶细胞分化的控制肾上腺素能 神经元输入;对比两种具有不同模式的组织， 受体个体发育应该使我们能够确定这些作用是否是 通用的或更确切地说是特定于选择性靶组织。