Neurotransmitter metabolism in intermittent hypoxia

间歇性缺氧中的神经递质代谢

• 批准号: 6580880
• 负责人: Ganesh K Kumar
• 金额: $ 24.88万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-01 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6580880
• 关键词: catecholamines; enzyme activity; gamma aminobutyrate; glutamate decarboxylase; hypoxia; laboratory rat; neural plasticity; neurotransmitter metabolism; oxygenases; phosphorylation; posttranslational modifications; respiratory hypoxia; substance P; tyrosine 3 monooxygenase

DESCRIPTION (provided by applicant): The overall objective of the proposal is to broadly define post-translational mechanisms associated with changes in the activity of enzymes regulate the biosynthesis of neurotransmitters by chronic intermittent hypoxia (CIH). Mechanisms associated with CIH contribute to various physiological and pathophysiological conditions such as sleep apnea and leads to the development of hypertension. Neurotransmitters such as catecholamines, gamma-aminobutyric acid and amidated neuropeptides involve in the modulation of cardio-respiratory responses. The proposal tests the overall hypothesis that intermittent hypoxia alters neurotransmitter levels in the chemoafferent pathway by affecting the activity of enzymes associated with the synthesis of neurotransmitters via post-translational modifications. The hypothesis will be tested by focusing on tyrosine hydroxylase (TH), glutamate decarboxylase (GAD) and peptidylglycine alpha-amidating monooxygenase (PAM) the rate-limiting enzymes in the biosynthesis of catecholamines, GABA and amidated neuropeptides respectively. The experiments in specific aim 1 will compare the changes in the content of catecholamines (norepinephrine, dopamine and 5- hydroxytryptamine) and the activity of TH by CIH. Further, it will test the hypothesis that CIH induces phosphorylation of TH, thereby altering the enzyme activity. Potential alteration in enzymological properties of TH will be examined. Studies proposed under specific aim 2 focus on the mechanisms by which the activity of GAD is altered by CIH. Specifically, the aims of the proposed studies are to define changes in cofactor affinity and phosphorylation and dephosphorylation reactions of GAD. In specific aim 3, the effects of CIH on the redox chemistry of metal centers containing Cu2+ and the post-translational endoproteolytic modification of PAM will be investigated. Experiments will be performed in rats exposed to alternating cycles of hypoxia and normoxia for defined periods of time and rats exposed to similar duration of room air will serve as control. Tissues associated with the chemoafferent pathway such as brainstem, and carotid body will be investigated. It is anticipated that the results from studies proposed in this project may provide important new information and broaden our understanding of the effects of episodic hypoxia on enzymes associated with neurotransmitter metabolism in the chemoafferent pathway. The information from these studies will have the potential to identify new therapeutic targets for the intervention of sleep disorders associated with recurrent intermittent hypoxia.

描述（由申请人提供）： 该提案的总体目标是广泛定义翻译后 与酶活性变化相关的机制调节 慢性间歇性缺氧（CIH）导致神经递质的生物合成。 与 CIH 相关的机制有助于各种生理和 病理生理条件，如睡眠呼吸暂停，并导致发展 高血压。神经递质，如儿茶酚胺、γ-氨基丁酸 酸性和酰胺化神经肽参与心肺功能的调节 回应。该提案检验了总体假设： 间歇性缺氧改变化学传入神经递质水平 通过影响与合成相关的酶的活性来实现途径 通过翻译后修饰产生神经递质。该假设将 重点测试酪氨酸羟化酶 (TH)、谷氨酸脱羧酶 (GAD) 和肽基甘氨酸 α-酰胺化单加氧酶 (PAM) 限速 儿茶酚胺、GABA 和酰胺化生物合成中的酶 分别是神经肽。具体目标1中的实验将进行比较 儿茶酚胺（去甲肾上腺素、多巴胺和5- 羟色胺）和 CIH 的 TH 活性。此外，它将测试 假设 CIH 诱导 TH 磷酸化，从而改变酶 活动。 TH 酶学特性的潜在改变将是 检查了。具体目标 2 下提出的研究重点关注以下机制： CIH 改变了 GAD 的活性。具体而言，该组织的目标 拟议的研究是为了定义辅因子亲和力的变化和 GAD 的磷酸化和去磷酸化反应。在具体目标 3 中， CIH 对含 Cu2+ 的金属中心氧化还原化学的影响 PAM 的翻译后内切蛋白水解修饰将是 调查了。实验将在暴露于交变环境的大鼠中进行 在规定的时间内进行缺氧和常氧循环，并将大鼠暴露于 类似的室内空气持续时间将作为对照。相关组织 脑干、颈动脉体等化学传入通路 调查了。预计中提出的研究结果 该项目可能会提供重要的新信息并扩大我们的研究范围 了解间歇性缺氧对相关酶的影响 化学传入途径中的神经递质代谢。信息 从这些研究中将有可能确定新的治疗靶点 用于干预与反复间歇性相关的睡眠障碍 缺氧。