Cerebral Response to Sustained Hypoxia

描述(由申请人提供)：我们的总体目标是了解全球脑缺氧的生理后果，以及正常的体内平衡机制失效是如何进展为疾病的。为了解决这个问题，首先有必要定义对脑缺氧的正常生理反应。脑缺氧是许多疾病过程(肺、心、脑血管)的结果，因此要研究脑内对缺氧本身的稳态机制，必须从潜在的多系统共存疾病中分离出来进行检测。在本方案中，我们使用高原低氧(急性高原病-AMS)作为孤立的持续性低氧的模型系统，以研究正常的生理反应机制。这一建议从传统的高原研究和脑生理学的功能磁共振研究中得出了假设。我们将从实验上测试这些现有的模型，以解释从低氧暴露到脑部疾病的进展。我们的具体目标是测量健康人对急性(6小时)、短期(2天)和持续(7天)低氧(PIO2=90 Torr)的正常脑生理反应，并确定对低氧的时间依赖的生理反应。使用脑生理的MRI测量(即脑血流量、CMRO2、脑脊液体积和水肿的变化)，我们将对模型的各个组件进行实验测试。为了系统地评估正常生理反应的时间进程，这些测量将在一系列急性和持续的低氧暴露下进行。测量将在相同的人类受试者队列中进行(包括AMS易感和AMS抵抗者)。这些研究将提供大脑对缺氧的生理反应的全面图景，以及为什么一些人能够更好地适应低氧水平-我们将为理解疾病患者对缺氧的不同反应奠定基础。设计合适的临床干预措施来治疗慢性脑缺氧性下降取决于对这种全面的理解。

DESCRIPTION (provided by applicant): Our overall goal is to understand the physiological consequences of global cerebral hypoxia, and how failure of the normal homeostatic mechanisms progresses to disease. To address this, it is first necessary to define the normal physiological responses to cerebral hypoxia. Cerebral hypoxia is the outcome of many disease processes (pulmonary, cardiac, cerebrovascular), and thus to investigate cerebral homeostasis mechanisms to hypoxia per se, it is important to examine them in isolation from potentially coexistent multi-system disease. In this proposal we use altitude-induced hypoxia (Acute Mountain Sickness - AMS) as a model system of isolated sustained hypoxia to study the normal physiological response mechanisms. This proposal draws hypotheses from traditional high altitude research and from functional MRI studies of cerebral physiology. We will experimentally test these existing models to explain the progression from hypoxic exposure to cerebral disease. Our specific aims are to measure the normal cerebral physiological response to acute (<6 hrs), short-term (2 days) and sustained (7 days) hypoxia (PIO2 = 90 Torr) in healthy individuals, and define the time-dependent physiologic response to hypoxia. Using MRI measurements of cerebral physiology (i.e. changes in CBF, CMRO2, CSF volume & edema) we will experimentally test individual components of the models. To systematically assess the time-course of the normal physiological responses, these measurements will be made over a range of acute and sustained hypoxic exposure. Measurements will be made in the same cohort of human subjects (encompassing AMS-susceptible andAMS-resistant individuals). These studies will provide a comprehensive picture of the cerebral physiological responses to hypoxia, and why some individuals are better able to acclimatize to low oxygen levels-we will establish a basis for understanding why patients with disease respond differently to hypoxia. Designing appropriate clinical interventions to treat chronic cerebral hypoxic decline hinges on such a comprehensive understanding.