Brain Oxygen and Metabolism in Cardiopulmonary Bypass

心肺绕道中的脑氧和代谢

• 批准号: 7184343
• 负责人: Anna Pastuszko
• 金额: $ 37.57万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7184343
• 关键词: Affect; Animals; Biochemical; Biochemical Pathway; Biochemistry; Blood flow; Brain; Brain Injuries; Bypass; CREB1 gene; Cardiopulmonary Bypass; Cardiovascular system; Cell Death; Cells; Cerebrum; Congenital Abnormality; Corpus striatum structure; Coupled; Defect; Development; Dopamine; Dopamine D2 Receptor; Evaluation; Event; Free Radicals; Goals; Heart; Hypoxia; Infant; Injury; Laboratories; Measurement; Measures; Metabolic; Metabolism; Methods; Molecular; Monoamine Oxidase Inhibitors; Neurologic; Neuronal Injury; Newborn Infant; Numbers; Operative Surgical Procedures; Optical Methods; Oxygen; Pargyline; Patients; Perfusion; Phosphorylation; Procedures; Process; Production; Protein Dephosphorylation; Range; Rate; Recovery; Relative (related person); Role; Standards of Weights and Measures; Testing; Time; Tissues; Tyrosine; Work; blood flow measurement; brain metabolism; cell injury; extracellular; improved; inhibitor/antagonist; injured; neurotoxic; phosphorescence; prevent; receptor; relating to nervous system; tissue oxygenation

DESCRIPTION (provided by applicant): Birth defects of the heart and circulatory system affect more infants than any other type of birth defect. Of all infants born each year, approximately 1 in 115 has heart and/or circulatory defects and most of them require cardiopulmonary bypass surgery. Despite remarkable advances in surgery, a substantial fraction of these patients manifest neurological and developmental abnormalities. The cellular and molecular mechanisms of neurologic injury in the newborn brain, associated with DHCA, are poorly understood. In proposed studies, oxygen dependent quenching of phosphorescence, a noninvasive optical method for measuring oxygen developed in our laboratory, will be used to measure the oxygen in the microvasculature of the brain of newborn piglets. This method allows for the first time continuous evaluation of the status of tissue oxygenation DHCA and post-arrest recovery. The oxygen histograms will be coupled with measurements of the blood flow, status of brain metabolism and the extent of brain injury. Our study will determine the dopamine dependent mechanisms of neuronal injury within the striatum. We will also evaluate some promising approaches in the protection of the brain from neuronal injury caused by DHCA. This proposal has two major goals: (a) To determine the role of dopamine and dopamine dependent biochemical and molecular alterations on striatal injury following circulatory arrest. (b) To identify potential strategies for neural protection, particularly in striatum, following circulatory arrest. To achieve these goals, we will test the following specific aims: 1. Hypoxia induced increase in extracellular levels of dopamine in the striatum during DHCA is a major contributor of neuronal injury in the striatum of newborn piglets. 2. Dopamine exerts a neurotoxic effect in striatum of newborn piglets by increasing production of free radicals during post-arrest period. 3. Increased extracellular dopamine in the striatum, acting through the D1 and D2 receptors, alters a cascade of key regulatory processes that contribute substantially to neuronal injury induced by DHCA. 4. During DHCA, brain oxygen deficiency results in a massive increase in extracellular dopamine and brain injury, and this can be prevented by selective cerebral perfusion (SCP). 5. Dopamine dependent striatal injury from prolonged periods of DHCA can be decreased with intermittent brief rescue periods of LFCPB.

描述（由申请人提供）：心脏和循环系统的先天缺陷会影响婴儿更多的婴儿。在每年出生的所有婴儿中，大约有115分的心脏和/或循环缺陷，其中大多数需要心肺旁路手术。尽管手术取得了显着进步，但这些患者中有很大一部分表现出神经系统和发育异常。与DHCA相关的新生大脑中神经系统损伤的细胞和分子机制知之甚少。在拟议的研究中，磷光的依赖性淬灭是一种用于测量实验室中开发的氧气的非侵入性光学方法，用于测量新生小猪大脑微脉管系统中的氧气。该方法允许首次连续评估组织氧合DHCA的状态和逮捕后恢复。氧直方图将与血液流动的测量，脑代谢状态和脑损伤程度相结合。我们的研究将确定纹状体内神经元损伤的多巴胺依赖性机制。我们还将评估一些有前途的方法，以保护大脑免受DHCA引起的神经元损伤。 该提议有两个主要目标： （a）确定多巴胺和多巴胺依赖性的生化和分子改变循环停滞后纹状体损伤的作用。 （b）确定循环逮捕后的神经保护的潜在策略，特别是在纹状体中。 为了实现这些目标，我们将测试以下特定目标： 1。缺氧在DHCA期间在纹状体中诱导的细胞外多巴胺水平增加是新生小猪纹状体中神经元损伤的主要因素。 2。多巴胺在新生小猪的纹状体中发挥神经毒性作用，通过增加抢劫后自由基的产生。 3。通过D1和D2受体作用的纹状体中细胞外多巴胺增加，改变了一系列关键调节过程，这些过程对DHCA诱导的神经元损伤产生了重大贡献。 4。在DHCA期间，脑氧缺乏会导致细胞外多巴胺和脑损伤的大量增加，并且可以通过选择性脑灌注（SCP）来预防。 5。随着LFCPB的间歇性短暂救援期，可以减少多巴胺依赖性纹状体损伤。