Neurotransmitter metabolism in intermittent hypoxia

描述(由申请人提供)： 该提案的总体目标是广义地定义翻译后 与酶活性变化相关的机制调节 慢性间歇性低氧(CIH)对神经递质的生物合成 与脑出血相关的机制有助于不同的生理和 睡眠呼吸暂停等病理生理条件并导致发展 高血压的症状。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，即 间歇性低氧改变化学传入神经递质水平 通过影响与合成有关的酶的活性来实现 通过翻译后修饰的神经递质。这一假说将 通过重点检测酪氨酸羟基酶(TH)、谷氨酸脱羧酶 (GAD)和肽甘氨酸α-酰胺化单加氧酶(PAM)的限速作用 儿茶酚胺、GABA和酰胺化生物合成中的酶 分别为神经肽。在特定目标1中的实验将比较 儿茶酚胺(去甲肾上腺素、多巴胺和5-羟色胺)含量的变化。 羟色胺)和CIH法测定TH的活性。此外，它还将测试 假设CIH诱导TH的磷酸化，从而改变酶 活动。TH的酶学性质可能会发生改变 检查过了。在具体目标2项下提出的研究重点是 其中GAD的活性被CIH改变。具体地说， 建议的研究是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， ClH对含Cu2+和Cu2+金属中心氧化还原化学的影响 PAM的翻译后蛋白水解性修饰将是 调查过了。实验将在暴露于交变辐射的大鼠身上进行。 特定时间段的低氧和常氧循环以及暴露于 类似的房间空气持续时间将作为控制。与以下物质相关的组织 脑干、颈动脉小体等化学传入通路 调查过了。预计从研究中提出的结果 该项目可能会提供重要的新信息，并扩大我们的 了解间歇性低氧对相关酶的影响 化学传入通路中的神经递质代谢。这些信息 将有可能确定新的治疗靶点 对与反复发作的间歇性睡眠障碍有关的干预 缺氧。

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.