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: 3311155
• 负责人: THEODORE A SLOTKIN
• 金额: $ 17.1万
• 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 1992-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3311155
• 关键词: adrenal medulla; beta adrenergic receptor; catecholamines; drug adverse effect; drug metabolism; growth /development; laboratory rat; lung; neural information processing; neural transmission; neurochemistry; neurogenesis; neuropharmacologic agent; neurotransmitter metabolism; pediatric pharmacology; perinatal; peripheral nervous system; respiratory function; respiratory system; sympathetic nervous system; synapses

Catecholamines serve a dual role in the perinatal period, mediating vital physiological responses which are necessary to survive the adaptation to extrauterine life, as well as serving as potential trophic factors regulating cellular development in adrenergic target tissues. The current proposal examines both of these roles in the developing lung, a tissue where we have already shown that beta-receptor-mediated responses are critical to survival. Three basic questions will be addressed: 1. How do catecholamines derived from sympathetic innervation or the adrenal medulla influence the adaptation of the lung to air- breathing in the perinatal period? 2. How do catecholamines influence the replication and differentiation of lung tissue during development? 3. How do pharmacological treatments designed to promote neonatal respiratory function, influence development of catecholamine targets elsewhere in the body, with particular attention to the central nervous system? In all these cases, we will examine normal development and five perturbation models: peripheral sympathectomy (neonatal treatment with 6-hydroxydopamine s.c.), interference with central catecholaminergic development (intracisternal 6- hydroxydopamine), prenatal exposure to agents used to promote respiratory function in the newborn (late gestational maternal treatment with a beta 2-agonist, terbutaline, or a glucocorticoid, betamethasone), or prenatal exposure to beta-receptor blockade (late gestational maternal infusion of propranolol). For each model, biochemical profiles will be evaluated which assess development of tissue responsiveness to catecholamines (beta- receptor binding sites, beta-receptor-mediated responses), development of sympathetic innervation (nerve terminals, biosynthetic enzymes, norepinephrine release capabilities, sympathetic reflex competence), and onset of tonic regulation of lung sympathetics by the CNS. This will be followed by studies of the normal ontogenetic pattern and responsiveness to catecholamines and sympathetic stimulation of biochemical indices of cellular maturation of lung tissue (ornithine decarboxylase, polyamines, nucleic acid and protein synthesis and levels); for each perturbation model, we will assess the impact of altered adrenergic input on cellular development in the lung, as well as comparing these with adrenergic targets in the CNS, where catecholamines have been postulated to play a trophic role in differentiation and synaptogenesis.

儿茶酚胺在围产期起双重作用， 介导重要的生理反应， 生存适应子宫外的生活，以及作为 调节细胞发育的潜在营养因子 肾上腺素能靶组织。 目前的提案审查了 在发育中的肺中的这些作用， 表明β受体介导的反应对于 生存 将讨论三个基本问题： 1. 交感神经支配如何产生儿茶酚胺 或肾上腺髓质影响肺对空气的适应 围产期的呼吸 2. 儿茶酚胺如何影响复制和 肺组织在发育过程中的分化？ 3. 药物治疗如何促进 新生儿呼吸功能，影响发育 儿茶酚胺的目标在身体的其他地方，特别是 注意中枢神经系统？ 在所有这些情况下，我们将检查正常的发展和五个 扰动模型：外周交感神经切除术（新生儿 用6-羟基多巴胺皮下处理），干扰 中央儿茶酚胺能发育（脑池内6- 羟多巴胺），产前暴露于用于促进 新生儿呼吸功能（晚期妊娠母亲 用β 2-激动剂、特布他林或糖皮质激素治疗， β受体阻滞剂）或产前暴露于β受体阻滞剂 (late妊娠期母体输注普萘洛尔）。 为每个 模型，将评估生化特征， 组织对儿茶酚胺（β- 受体结合位点，β-受体介导的反应）， 交感神经支配的发展（神经末梢， 生物合成酶，去甲肾上腺素释放能力， 交感神经反射能力），和紧张性调节的开始， 肺交感神经系统。 随后将进行以下研究： 正常的个体发育模式和对 儿茶酚胺和交感神经刺激的生化 肺组织细胞成熟指数（鸟氨酸 脱羧酶、多胺、核酸和蛋白质合成， 水平）;对于每个扰动模型，我们将评估 改变肾上腺素能输入对肺细胞发育，如 并将其与中枢神经系统中的肾上腺素能靶点进行比较， 在那里，儿茶酚胺被假定起营养作用， 在分化和突触发生中的作用。