DRUGS AND DEVELOPMENT OF THE ADRENERGIC NERVOUS SYSTEM

儿茶酚胺在围产期有双重作用， 调节重要的生理反应，这些反应是 在适应宫外生活的过程中幸存下来，并担任 调节细胞发育的潜在营养因子 肾上腺素能靶组织。目前的提案审查了两项 这些在发育中的肺中的作用，我们已经在那里的组织 研究表明，β受体介导的反应对 生死存亡。将讨论三个基本问题： 1.交感神经如何产生儿茶酚胺 或肾上腺髓质影响肺对空气的适应- 在围产期呼吸？ 2.儿茶酚胺如何影响复制和 发育过程中肺组织的分化？ 3.旨在促进 新生儿呼吸功能，对发育的影响 儿茶酚胺在体内其他部位的靶标，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：周围交感神经切除术(新生儿 用6-羟基多巴胺治疗)，干扰 中枢儿茶酚胺能发育(脑池内6- 羟基多巴胺)，产前暴露于用于促进 新生儿的呼吸功能(妊娠晚期母亲 使用β2-激动剂、特布他林或糖皮质激素治疗， 倍他米松)，或产前暴露于β受体阻滞剂 (孕晚期母体输注心得安)。对于每个 模型，生化图谱将被评估，以评估 组织对儿茶酚胺反应性的发展(β- 受体结合部位、β受体介导的反应)、 交感神经的发育(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 中枢神经系统的肺交感神经。在此之后，将研究 正常个体发育模式和对 儿茶酚胺与生物化学的交感兴奋 肺组织细胞成熟指标(鸟氨酸 脱羧酶、多胺、核酸和蛋白质合成以及 水平)；对于每个扰动模式，我们将评估 改变肾上腺素能输入对肺细胞发育的影响，如 将这些与中枢神经系统中的肾上腺素能靶标进行比较， 儿茶酚胺被认为具有营养作用 在分化和突触发生方面。

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.