DEVELOPMENTAL REGULATION OF HYPERCAPNIC RESPONSES

高碳酸反应的发育调节

• 批准号: 6794599
• 负责人: RICHARD JOHN MARTIN
• 金额: $ 31.11万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6794599
• 关键词: GABA receptor; adenosine; age difference; alpha adrenergic receptor; apnea; autoradiography; brain stem; confocal scanning microscopy; gamma aminobutyrate; growth /development; hypercapnia; hypoxia; immunocytochemistry; in situ hybridization; inhibitor /antagonist; laboratory rat; neurons; pulmonary respiration; radiotracer; receptor expression; respiratory muscles; swine

DESCRIPTION (provided by applicant): Apnea of prematurity, which is a manifestation of immature centrally mediated respiratory control mechanisms, remains a troublesome problem in low birth weight infants. As a consequence large numbers of preterm infants receive therapy with xanthines, although their precise mechanism of action is not clearly understood. In the prior funding cycle of this proposal, we have demonstrated that ?-aminobutyric acid (GABA)-ergic pathways contribute greatly to the inhibition of respiratory timing that characterizes respiratory reflex responses in the newborn. As a natural continuation of this work, we now focus on the role of GABA in mediating the effects of adenosine on neonatal respiratory control. Our most recent preliminary data provide evidence in rat pups that adenosine A2A receptors are prominent in respiratory related areas of the brainstem, and present on GABA containing neurons. Furthermore, administration of A2A receptor agonists induces inspiratory inhibition, which is greatest in the youngest animals, and this effect is blocked by the GABAA receptor antagonist bicuculline. In this proposal we therefore seek to test the hypothesis that adenosine elicits inspiratory inhibition via activation of A2A receptors on GABA containing neurons, and that inhibition of inspiratory related neurons is secondary to increased GABAergic influences. In Aim 1 we hypothesize that these adenosine A2A/GABAergic interactions are greatest in early postnatal life. In Aim 2 we hypothesize that exposure to repetitive hypoxia and/or hypercapnia increases centrally mediated respiratory inhibition by increasing A2A receptor expression on GABAergic neurons and GABAA receptor expression on inspiratory related neurons at the medullary rhythm-generating site (preBtzinger complex, pBc). In both aims we will use neuroanatomic and physiologic studies, with which we have expertise, in maturing rats. The neuroanatomic studies will employ immunohistochemical and molecular techniques combined with retrograde tracers to identify the presence of A(2A) receptor at message and protein levels on respiratory related GABAergic neurons, and GABA(A) receptors at the medullary rhythm generating site (pBc). The physiologic studies will employ whole animals and in vitro medullary slices to measure phrenic and hypoglossal neural output, in addition to single unit recording, in response to application of adenosine receptor agonists with and without GABA(A) receptor blockade at targeted sites. These studies should shed new light on interaction between key inhibitory neurotransmitters during maturation of respiratory control, their role in the pathogenesis of neonatal apnea and our understanding of how a common pharmacologic strategy modulates these phenomena.

描述（由申请人提供）：早产呼吸暂停，这是未成熟中心介导的呼吸控制机制的表现，仍然是低出生体重婴儿的麻烦问题。结果，大量早产儿接受了黄嘌呤的治疗，尽管尚未清楚地理解其精确的作用机理。在该提案的先前资金周期中，我们证明了 - 氨基丁酸（GABA） - 能途径极大地有助于抑制新生儿呼吸反射反应的呼吸时机。作为这项工作的自然延续，我们现在专注于GABA在介导腺苷对新生儿呼吸控制作用中的作用。我们最近的初步数据在大鼠幼崽中提供了证据，表明腺苷A2A受体在脑干的呼吸相关区域很突出，并且存在于含有神经元的GABA上。此外，施用A2a受体激动剂会诱导最年轻的动物中最大的灵感抑制作用，并且这种作用被GABAA受体拮抗剂双瓜氨酸所阻断。因此，在该提案中，我们试图检验以下假设：腺苷通过激活含有神经元的GABA的A2A受体引起灵感抑制作用，并且抑制灵感相关神经元的抑制是GABA能量增加的影响。在AIM 1中，我们假设这些腺苷A2A/GABA能相互作用在产后早期生活中最大。在AIM 2中，我们假设暴露于重复性缺氧和/或过度capnia，通过增加对GABA能神经元上的A2A受体表达和GABAA受体表达来增加集中介导的呼吸抑制作用，并在髓质节奏点上的灵感相关神经元上表达在吸气性相关的神经元上（Preb-tzinger Complact，pbc）。在这两个目标中，我们都将使用神经解剖学和生理学研究，并在成熟的大鼠中具有专业知识。神经解剖学研究将采用与逆行示踪剂结合的免疫组织化学和分子技术，以在呼吸道相关的GABA能神经元和GABA（A）受体（A）受体（PBC）（PBC）上的呼吸与GABA（A）受体鉴定A（2a）受体的存在。 生理研究还将采用全动物和体外髓质切片来测量除单位记录外，除了单位记录外，还应响应在目标部位的腺苷受体受体激动剂的应用。这些研究应为关键抑制性神经递质在呼吸控制成熟期间，它们在新生儿呼吸暂停的发病机理中的作用以及我们对常见药理策略如何调节这些现象如何调节这些现象之间的作用。