Tissue Oxygenation and Cerebral Vulnerability to Hypoxia

组织氧合和大脑缺氧的脆弱性

• 批准号: 8303023
• 负责人: DAVID DUBOWITZ
• 金额: $ 23.23万
• 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 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8303023
• 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 PUBLIC HEALTH RELEVANCE: The brain has a high energy demand and a low tolerance for interruptions of oxygen availability. In this proposal we use novel MRI techniques to measure cerebral blood flow (CBF) oxygen metabolism (CMRO2) and tissue oxygenation (PtO2) to test our hypothesis that maintaining a high PtO2 is necessary for the health of the brain. 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.

描述（由申请人提供）：这些研究的长期目标是了解全球脑缺氧的生理后果，以及正常稳态机制的失败如何导致大脑疾病。人脑的能量需求很高，对氧气可用性中断的容忍度较低。我们的总体假设是，任何降低组织氧合（PTO2）都会导致大脑健康的逐渐降低，而不是仅当PTO2达到非常低的阈值水平时才受损。如果是真的，这个想法对导致脑损伤的多种疾病的管理和治疗具有影响，从而对其进行低氧成分。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。在人类中检验这一总体假设是挑战的。一旦发生低氧损伤，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模型。在我们最近研究人类受试者脑适应高海拔的研究中，我们发现尽管O2的可用性降低了，但在缺氧期间，脑O2代谢（CMRO2）仍会增加。由于Tisue PTO2受到脑血流（CBF）（供应O2）和CMRO2（删除O2）的直接影响，因此O2供需的这种矛盾的不匹配有可能操纵PTO2，从而测试我们PTO2在确定脑脑易蛋白质中的总体假设。我们在该项目中的目标是o使用新颖的MRI技术来测量CBF，CMRO2和PTO2来测试PTO2对人类受试者脑易感性易感性的影响。我们的第一个具体目的是检查角色 动脉PACO2解释急性低氧暴露期间CMRO2的增加。我们将测试在常氧和低氧条件下如何高，正常和低二氧化碳影响CMRO2。我们的第二个具体目的是测试受试者是否容易受到低氧脑ilnes的影响（表现为对急性山地疾病的易感性-AMS），在暴露于缺氧条件下，组织PTO2的下降比对AMS耐药性受试者的下降更大。这一系列的研究将测试我们对缺氧的矛盾CMRO2反应模型，以此作为影响组织氧合的一种手段，从此决定了高组织氧合对赋予对脑缺氧性耐药性的重要性。 公共卫生相关性：大脑的能量需求很高，对氧气可用性中断的容忍度较低。在此提案中，我们使用新颖的MRI技术来测量脑血流（CBF）氧代谢（CMRO2）和组织氧合（PTO2）来检验我们的假设，即维持高PTO2对于大脑的健康是必不可少的。如果是真的，这 想法对导致脑损伤的多种疾病的管理和治疗具有影响，这对它们具有低氧成分。