Tissue Oxygenation and Cerebral Vulnerability to Hypoxia

组织氧合和大脑缺氧的脆弱性

• 批准号: 8418707
• 负责人: DAVID DUBOWITZ
• 金额: $ 18.7万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-15 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8418707
• 关键词: Acclimatization; Acute; Address; Adenosine; Affect; Altitude; Altitude Sickness; Basal Ganglia; Brain; Brain Injuries; Carbon Dioxide; Cardiac Surgery procedures; Cerebral Hypoxia; Cerebrovascular Circulation; Cerebrum; Deterioration; Disease; Drops; Energy Metabolism; Equilibrium; Exhibits; Exposure to; Failure; Financial compensation; Foundations; Future; Goals; Health; Heart Arrest; Hippocampus (Brain); Human; Hypercapnia; Hypocapnia; Hypoxia; Impairment; Individual; Injury; Interruption; Ischemic Stroke; Link; Magnetic Resonance Imaging; Measures; Metabolic; Metabolism; Methods; Modeling; Oxygen; Pathway interactions; Physiological; Physiology; Population Study; Predisposition; Process; Resistance; Role; Series; Stroke; Techniques; Testing; Tissue Model; Tissue Survival; Tissues; Traumatic Brain Injury; Work; brain tissue; cohort; design; human subject; neuronal excitability; novel; prevent; response; tissue oxygenation

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

描述（由申请方提供）：这些研究的长期目标是了解全脑缺氧的生理后果，以及正常稳态机制的失效如何导致脑疾病。人类大脑具有高能量需求和对氧气供应中断的低耐受性。我们的总体假设是，组织氧合（PtO 2）的任何降低都会导致大脑健康的逐步恶化，而不是只有当PtO 2达到非常低的阈值水平时才受到损害。如果属实，这一想法将对管理和治疗多种导致脑损伤且含有缺氧成分的疾病产生影响。在这种情况下，决定损伤的关键因素是组织氧合降低的程度。在人类中测试这一整体假设是具有挑战性的;一旦发生缺氧损伤，正常的生理反应就会改变，因此我们需要一个没有伴随疾病的组织缺氧生理模型。在我们最近的研究中，我们发现，脑氧代谢（CMRO 2）增加，尽管减少氧气供应的高海拔地区的人类受试者的大脑习服。由于组织PtO 2直接受到脑血流量（CBF）（提供O2）和CMRO 2（去除O2）的影响，这种O2供需矛盾的不匹配有可能操纵PtO 2，从而检验我们关于PtO 2在确定脑缺氧脆弱性中的核心作用的总体假设。本研究的目的是利用新的MRI技术测量脑血流量（CBF）、CMRO_2和PtO_2，以检测PtO_2对人类受试者大脑缺氧敏感性的影响。我们的第一个具体目标是检查角色 的动脉PaCO 2解释急性缺氧暴露期间CMRO 2的增加。我们将测试在常氧和低氧条件下高、正常和低CO2对CMRO 2的影响。我们的第二个具体目标是测试易患缺氧性脑病的受试者（表现为对急性高山病的易感性- AMS）在暴露于缺氧条件时是否比AMS抵抗受试者显示出更大的组织PtO 2下降。这一系列的研究将测试我们的CMRO 2对缺氧的反常反应模型作为影响组织氧合的手段，并由此确定高组织氧合对于赋予对脑缺氧疾病的抵抗力的重要性