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(申请人提供)：这些研究的长期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的失败如何导致脑部疾病。人脑对能量的需求很高，对氧气供应中断的耐受性很低。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造成损害。如果这是真的，这个想法对于管理和治疗一系列导致脑损伤的疾病具有重要意义，这些疾病都有缺氧成分。在这种情况下，决定损伤的关键因素是组织氧合降低的程度。在人类身上验证这一总体假设是令人兴奋的；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的生理学模型。在我们最近对人类大脑对高原习服的研究中，我们发现在低氧条件下，尽管氧气利用率降低，但大脑氧代谢(CMRO2)增加。由于PtO2直接受到脑血流量(CBF)(供应O2)和CMRO2(去除O2)的影响，这种矛盾的O2供需不匹配有可能操纵PtO2，从而检验我们关于PtO2在确定大脑对低氧的易感性方面的中心作用的总体假设。我们在这个项目中的目标是使用新的MRI技术来测量CBF、CMRO2和PtO2，以测试PtO2对人类大脑对低氧敏感性的影响。我们的第一个具体目标是检查角色 动脉血二氧化碳分压的变化解释急性低氧暴露时CMRO2升高的原因。我们将测试常氧和低氧条件下的高、正常和低二氧化碳对CMRO2的影响。我们的第二个具体目标是测试易患缺氧性脑ILN(表现为易患急性高原反应-AMS)的受试者在暴露于低氧条件下的组织PtO2是否比耐AMS的受试者下降得更大。这一系列研究将测试我们的CMRO2对低氧的矛盾反应模型，以此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增强对脑缺氧性疾病的抵抗力的重要性。