Integrative Consequences of Hypoxia

描述（由申请人提供）： 这是一个竞争性的更新申请的计划项目赠款题为“综合后果的缺氧”。该计划的总体重点是继续研究慢性间歇性缺氧（CIH）的全身，细胞和分子反应的影响。竞争性更新申请的首要假设是：a）ROS通过在化学反射途径的各个组分（传感器、控制器和终末器官）中招募不同的细胞机制来影响化学反射功能;和B）长期暴露于CIH导致ROS以及心脏呼吸功能的稳定变化，并涉及化学反射途径中氧化还原稳态的表观遗传调节。项目1将检验以下假设：CIH对颈动脉体的影响是由于ROS介导的抑制性（一氧化碳; CO）和兴奋性（硫化氢; H2S）气体信使之间的不平衡。项目2检验了CIH引起的化学反射触发交感神经激活引起肾上腺髓质氧化应激的假设，肾上腺髓质是一个主要的交感神经终末器官，导致缺氧引起的儿茶酚胺分泌增加，这有助于CIH诱导的高血压。项目3测试了ClH诱导的不规则呼吸是由颈动脉体依赖性ROS产生和PreBotC中呼吸神经网络的重构介导的假设。项目4检验了这样一个假设，即化学反射途径中编码氧化还原调节酶的基因的表观遗传调节有助于持续的氧化应激和对长期CIH的心肺反应。核心活动A履行行政和协调职能。CORE B为所有四个项目提供集中设施，使啮齿动物接触CIH，维持转基因小鼠，进行形态学、生物化学和分子生物学测定。由于项目之间紧密的主题联系，从整个计划中获得的总知识将真正大于每个项目的总和。

DESCRIPTION (Provided by applicant): This is a competing renewal application of the Program Project Grant entitled "INTEGRATIVE CONSEQUENCES OF HYPOXIA". The overall focus of the Program continues to examine the effects of systemic, cellular and molecular responses to chronic intermittent hypoxia (CIH). The overarching hypotheses of the competing renewal application are: a) ROS affect chemo reflex function by recruiting distinct cellular mechanisms in the individual components of the chemo reflex pathway (sensor, controller, and end organ); and b) Long-term exposure to CIH leads to stable changes in ROS as well as cardio respiratory functions and involves epigenetic regulation of redox homeostasis in the chemo reflex pathway. PROJECT 1 will test the hypothesis that the effects of CIH on the carotid body are due to ROS-mediated imbalance between inhibitory (carbon monoxide; CO) and excitatory (hydrogen sulfide; H2S) gaseous messengers. PROJECT 2 tests the hypothesis that chemo reflex triggered sympathetic activation by CIH evokes oxidative stress in the adrenal medulla, a major sympathetic end organ resulting in augmented catecholamine secretion by hypoxia, which contributes to ClH-induced hypertension. PROJECT 3 tests the hypothesis that the ClH-induced irregular breathing is mediated by carotid body-dependent ROS generation and reconfiguration of the respiratory neural network in the PreBotC. PROJECT 4 tests the hypothesis that epigenetic regulation of genes encoding redox regulatory enzymes in the chemo reflex pathway contributes to persistent oxidative stress, and the cardio-respiratory responses to long-term CIH. CORE A fulfills an administrative and coordinating function. CORE B provides centralized facilities for exposure of rodents to CIH, maintenance of genetically modified mice, morphological, biochemical and molecular biological assays for all four projects. Because of the tight thematic linkages across the projects, the total knowledge gained from the overall program will truly be greater than the sum derived from each project.