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，以及正常稳态机制的失败如何导致脑疾病。人脑的能量需求较高，但对氧气供应中断的耐受性较低。我们的总体假设是，组织氧合 (PtO2) 的任何降低都会导致大脑健康状况逐渐恶化，而不是仅当 PtO2 达到非常低的阈值水平时才会出现损害。如果属实，这个想法对于管理和治疗多种导致脑损伤的疾病具有重要意义，这些疾病具有缺氧成分。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。在人类身上检验这一总体假设具有挑战性。一旦发生缺氧损伤，正常的生理反应就会发生改变，因此我们需要一个不伴随疾病的组织缺氧的生理模型。在我们最近研究人类受试者对高海拔的大脑适应过程中，我们发现，尽管氧气供应量减少，但在缺氧期间，大脑氧气代谢 (CMRO2) 会增加。由于组织 PtO2 直接受到脑血流 (CBF)（供应 O2）和 CMRO2（去除 O2）的影响，这种 O2 供需矛盾的不匹配有可能操纵 PtO2，从而检验我们关于 PtO2 核心作用的总体假设。 PtO2 确定大脑对缺氧的脆弱性。我们本项目的目标是使用新型 MRI 技术测量 CBF、CMRO2 和 PtO2，以测试 PtO2 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 动脉 PaCO2 的变化来解释急性缺氧暴露期间 CMRO2 的增加。我们将测试常氧和缺氧条件下高、正常和低 CO2 对 CMRO2 的影响。我们的第二个具体目标是测试易患缺氧性脑病（表现为对急性高山病 - AMS 的易感性）的受试者在暴露于缺氧条件时是否表现出比抗 AMS 受试者更大的组织 PtO2 下降。这一系列研究将测试我们的自相矛盾的 CMRO2 对缺氧反应的模型作为影响组织氧合的一种手段，并由此确定高组织氧合对于赋予抵抗脑缺氧疾病的重要性