Cerebral Response to Sustained Hypoxia

描述（由申请人提供）：我们的总体目标是了解全脑缺氧的生理后果，以及正常稳态机制的失败如何发展为疾病。为了解决这个问题，首先有必要确定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，因此为了研究脑缺氧自身的稳态机制，重要的是将它们与潜在共存的多系统疾病分开检查。本研究以高原缺氧（Acute Mountain Sickness，AMS）为模型系统，研究高原缺氧的正常生理反应机制。该建议从传统的高海拔研究和脑生理学的功能性MRI研究中得出假设。我们将通过实验测试这些现有的模型来解释从缺氧暴露到脑疾病的进展。我们的具体目标是测量健康个体对急性（<6小时）、短期（2天）和持续（7天）缺氧（PIO 2 = 90 Torr）的正常脑生理反应，并定义对缺氧的时间依赖性生理反应。使用脑生理学的MRI测量（即CBF，CMRO2，CSF体积和水肿的变化），我们将通过实验测试模型的各个组件。为了系统地评估正常生理反应的时程，将在急性和持续低氧暴露的范围内进行这些测量。将在同一组人类受试者（包括AMS敏感和AMS耐药个体）中进行测量。这些研究将提供大脑对缺氧的生理反应的全面图景，以及为什么有些人能够更好地适应低氧水平，我们将建立一个基础，了解为什么疾病患者对缺氧的反应不同。设计适当的临床干预措施来治疗慢性脑缺氧下降取决于这样一个全面的理解。

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.