Integrative Consequences of Hypoxia

描述(由申请人提供)： 本申请是为一项名为“缺氧的综合后果”的新项目拨款而提出的。间歇性低氧(IH)是一种常见的危及生命的疾病，与许多不同的疾病有关，包括睡眠呼吸紊乱和反复呼吸暂停。反复发生的呼吸暂停是美国人口发病率和死亡率的主要原因，估计有1800万成年人和50%的早产儿受到影响。未来五年，这项拟议研究的总体目标是检查慢性高血压的生理后果。反复发生呼吸暂停的患者会出现严重的心肺疾病，表现为高血压、交感神经活动增强和呼吸异常。当前建议的一个重要假设是，IH导致控制心肺系统内稳态的促进机制和抑制机制之间的不平衡，从而导致发病率。使用体内和体外的IH模型，当前计划中的所有四个项目都在不同程度上检验了这一假说。慢性高血压导致外周化学感受器反射的上调和压力感受器反射的下调，从而导致交感神经活性的无对抗升高。因此，项目1旨在确定与颈动脉小体化学感受器功能增强相关的细胞和分子机制，而项目2则研究慢性高血压下调压力感受器反射的细胞和分子机制(S)。项目3确定了慢性IH对Boetzinger前复合体中调节呼吸频率和潮汐神经活动的神经元的网络和膜特性的影响，这可能有助于呼吸的改变。IH改变了促氧化剂和抗氧化剂之间的平衡，导致细胞内活性氧物种(ROS)的增加，从而放大了短暂的低氧信号，并将其转化为全身反应。项目1、2、3研究了HIF-1转录激活剂在IH诱导的促氧化剂上调中的作用，而项目4评估了HIF-2在化疗和压力反射通路中慢性IH诱导的抗氧化剂下调中的作用。核心A履行管理和协调职能。核心B为啮齿动物暴露在CIH中，维持转基因小鼠群体提供中央设施，为所有四个项目进行形态、生物化学和分子生物学分析。从拟议的综合方法中出现的概念框架为心肺系统的功能重组提供了新的见解，这对于理解与睡眠呼吸障碍相关的高血压的后果具有翻译意义。该计划的综合性和综合性提供了最大的合作努力，并增强了最终从该计划中产生的知识的影响。我们相信，这些研究积累的全部知识将真正超过每个项目的总和，因为各项目之间有密切的主题联系。

DESCRIPTION (provided by applicant): This application is for a new Program Project Grant entitled "INTEGRATIVE CONSEQUENCES OF HYPOXIA". Intermittent Hypoxia (IH) is a common and life threatening condition associated with many different diseases including sleep-disordered breathing with recurrent apneas. IH associated with recurrent apneas is a major cause of morbidity and mortality in the U.S. population, affecting an estimated 18 million adults and 50% of premature infants. The overall objective of the proposed study for the next five years is to examine the physiological consequences of chronic IH. Patients with recurrent apneas develop serious cardio-respiratory morbidities manifested as hypertension, augmented sympathetic activity, and abnormalities in breathing. An overarching hypothesis of the current proposal is that IH leads to an imbalance between facilitatory and inhibitory mechanisms that govern homeostasis of the cardio-respiratory systems resulting in morbidity. Using in vivo and in vitro models of IH, all four projects in the current program albeit to different degrees test this hypothesis. Chronic IH leads to up-regulation of peripheral chemoreceptor reflex and down-regulation of baroreceptor reflex resulting in unopposed elevation of sympathetic nerve activity. Therefore, Project 1 aims at identifying the cellular and molecular mechanisms associated with augmented carotid body chemoreceptor function, whereas Project 2 examines the cellular and molecular mechanism(s) underlying the down-regulation of baroreceptor reflex by chronic IH. Project 3 determines the impact of chronic IH on network and membrane properties of the neurons in pre-Boetzinger complex that regulate the respiratory rate and tidal neural activities, which may contribute to changes in breathing. IH alters the balance between pro- and anti-oxidants resulting in increased cellular reactive oxygen species (ROS), which amplify the brief hypoxic signals and translate them to systemic responses. Projects 1,2,3 examine the role of HIF-1 transcriptional activator on IH-evoked up-regulation of pro-oxidants, whereas Project 4 assesses the contribution of HIF-2 to chronic IH- evoked down-regulation of anti-oxidants in chemo and baro-reflex pathways. Core A fulfills an administrative and coordinating function. Core B provides central facilities for exposure of rodents to CIH, maintenance of genetically modified mice colony carrying out morphological, biochemical and molecular biological assays for all four projects. The conceptual frame work emerging from the proposed integrated approaches provide novel insights into the functional reorganization of the cardio-respiratory systems, which is of translational significance in understanding the consequences of IH associated with sleep-disordered breathing. The integrative and comprehensive nature of this Program offers maximal collaborative efforts and enhances the impact of knowledge that eventually emerges from this Program. We are confident that the total knowledge accrued from these studies will truly be greater than the sum of each project because of the tight thematic linkages across the projects.