Brain Oxygen and Metabolism in Cardiopulmonary Bypass

描述（由申请人提供）：心脏和循环系统的出生缺陷比任何其他类型的出生缺陷影响更多的婴儿。在每年出生的所有婴儿中，大约每115名中就有1名患有心脏和/或循环系统缺陷，其中大多数需要进行心肺转流手术。尽管在手术方面取得了显着的进步，这些患者中有相当一部分表现出神经和发育异常。与DHCA相关的新生儿脑神经损伤的细胞和分子机制知之甚少。在拟议的研究中，氧依赖的磷光猝灭，在我们的实验室开发的一种非侵入性的光学方法测量氧气，将被用来测量新生仔猪的大脑的微血管中的氧气。该方法允许第一次连续评估组织氧合DHCA和停搏后恢复的状态。氧气直方图将与血流、脑代谢状态和脑损伤程度的测量相结合。我们的研究将确定纹状体内神经元损伤的多巴胺依赖机制。我们还将评估一些有前途的方法，在保护大脑从DHCA引起的神经元损伤。 这项建议有两个主要目标： (a)确定多巴胺和多巴胺依赖性生化和分子改变在循环停止后纹状体损伤中的作用。 (b)确定循环停止后神经保护的潜在策略，特别是纹状体。 为了实现这些目标，我们将测试以下具体目标： 1.缺氧诱导的细胞外多巴胺水平的增加在纹状体DHCA期间是一个主要的贡献者在新生仔猪的纹状体神经元损伤。 2.多巴胺在新生仔猪纹状体中通过增加自由基的产生而发挥神经毒性作用。 3.纹状体中细胞外多巴胺的增加，通过D1和D2受体起作用，改变了一系列关键的调节过程，这些过程对DHCA诱导的神经元损伤有很大贡献。 4.在DHCA期间，脑缺氧导致细胞外多巴胺大量增加和脑损伤，这可以通过选择性脑灌注（SCP）来预防。 5.通过LFCPB的间歇性短暂挽救期，可以减少长时间DHCA引起的多巴胺依赖性纹状体损伤。

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.