Tissue Oxygenation and Cerebral Vulnerability to Hypoxia

描述（由申请人提供）：这些研究的长期目标是了解全脑缺氧的生理后果，以及正常体内平衡机制的失败如何导致脑疾病。人脑对能量的需求很高，对氧气供应中断的容忍度很低。我们的总体假设是，任何组织氧合（PtO2）的降低都会导致大脑健康的进行性恶化，而不是只有当PtO2达到非常低的阈值水平时才会出现损伤。如果这是真的，这一观点将对管理和治疗一系列引起脑损伤的缺氧因素产生影响。在这种情况下，决定损伤的关键因素是组织氧合减少的程度。在人类身上验证这一整体假设是具有挑战性的；缺氧损伤发生后，正常的生理反应发生改变，因此我们需要一种无伴发疾病的组织缺氧生理模型。在我们最近的研究中，我们调查了人类受试者的大脑对高海拔的适应情况，我们发现尽管氧气可用性降低，但缺氧时脑氧代谢（cmoo2）增加。由于组织PtO2直接受到脑血流量（CBF）（供应O2）和cmor2（去除O2）的影响，这种矛盾的氧气供需不匹配有可能操纵PtO2，从而验证了我们关于PtO2在决定大脑缺氧易易性中的核心作用的总体假设。我们在这个项目的目标是使用新的MRI技术来测量CBF， cmor2和PtO2，以测试PtO2对人类受试者大脑缺氧易感性的影响。我们的第一个具体目标是检查角色

DESCRIPTION (provided by applicant): The longterm goal of these studies is to understand the physiological consequences of global cerebral hypoxia, and how failure of the normal homeostatic mechanisms contributes to cerebral disease. The human brain has a high energy demand and a low tolerance for interruptions of oxygen availability. Our overall hypothesis is that any lowering of tissue oxygenation (PtO2) leads to a progressive deterioration of the health of the brain, rather than impairment only when PtO2 reaches very low threshold levels. If true, this idea has implications for the management and treatment of a wide range of conditions causing brain injury that have a hypoxic component to them. The critical factor that determines injury in this scenario is the degree to which tissue oxygenation decreases. Testing this overall hypothesis in humans is chalenging; the normal physiological responses are altered once hypoxic injury has occurred, thus we need a physiological model of tissue hypoxia without concomitant disease. During our recent studies investigating cerebral acclimatization to high altitude in human subjects, we found that Cerebral O2 metabolism (CMRO2) increases during hypoxia despite reduced O2 availability. Since tisue PtO2 is directly impacted by cerebral blood flow (CBF) (supplying O2) and CMRO2 (removing O2), this paradoxical mismatch of O2 supply and demand has the potential to manipulate PtO2 and thus to test our overall hypothesis of the central role of PtO2 in determining cerebral vulnerability to hypoxia. Our goal in this project is o use novel MRI techniques to measure CBF, CMRO2 and PtO2 to test the influence of PtO2 on cerebral susceptibility to hypoxia in human subjects. Our first Specific Aim is to examine the role of arterial PaCO2 to explain the increase of CMRO2 during acute hypoxic exposure. We wil test how high, normal and low CO2 during normoxic and hypoxic conditions impact CMRO2. Our second Specific Aim is to test if subjects vulnerable to hypoxic cerebral ilnes (manifest as susceptibility to acute mountain sickness - AMS) show a greater drop in tissue PtO2 on exposure to hypoxia conditions than AMS-resistant subjects. This series of studies will test our model of paradoxical CMRO2 response to hypoxia as a means to influence tissue oxygenation, and from this determine the importance of high tissue oxygenation for conferring resistance to cerebral hypoxic disease