Protection of Developing White Matter during Cardiac Surgery

心脏手术期间白质发育的保护

基本信息

批准号：
8662304
负责人：
RICHARD A JONAS
金额：
$ 62.4万
依托单位：
CHILDREN'S RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-15 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8662304
关键词：
Anti-Inflammatory Agents Anti-inflammatory Antibodies Attention Behavioral Brain Brain Injuries Bypass Cardiac Surgery procedures Cardiopulmonary Bypass Cell Lineage Cerebrum Child Child Development Childhood Clinical Research Clinical Trials Cognitive Congenital Abnormality Custom Development Glucose Goals Heart-Lung Machine Hemodilution Immunohistochemistry Incidence Inflammation Inflammatory Inflammatory Response Investigation Ischemia Laboratories Low Birth Weight Infant Magnetic Resonance Imaging Methods Modeling Motor Motor Skills Mus Myelin Neurons Neurosciences Newborn Infant Oligodendroglia Operative Surgical Procedures Outcome Oxygen Perfusion Play Predisposition Premature Infant Reperfusion Therapy Research Risk Slice Stress Study of magnetics Techniques Temperature Testing Transgenic Mice age related alkalinity congenital heart disorder cytokine experience improved oligodendrocyte precursor precursor cell prospective white matter white matter injury

项目摘要

DESCRIPTION (provided by applicant): Both prospective clinical trials and retrospective clinical studies of development of children following surgery for congenital heart disease have documented worse outcomes for motor skills than cognitive abilities. This finding is consistent with several recent studies using magnetic resonance imaging (MRI) in newborns and infants after cardiac surgery which have documented evidence of white matter injury (WMI). A presumed selective vulnerability of the newborn to WMI has led some to suggest that corrective surgery should be avoided in the newborn period despite its many advantages. Suspected causative factors of WMI in the newborn include a unique susceptibility to the deleterious effects of cardiopulmonary bypass (CPB) including an exaggerated systemic inflammatory response as well as a risk of ischemia/reperfusion. Bypass strategies that include rapid cooling, extreme hemodilution and severe alkalinity as well as some techniques of circulatory arrest have been documented to critically limit oxygen delivery. Considerable attention has been directed towards understanding white matter development because ultra-low birthweight premature infants are also susceptible to deficits in motor development and also demonstrate evidence of WMI by MRI. Immunohistochemistry methods and specifically developed transgenic mice allow identification of the cell lineage leading to mature oligodendrocytes which are responsible for the laying down of myelin. The proposed study will test the following hypotheses: i) There is an age-dependent susceptibility of white matter to the inflammatory effects of CPB, ii) There is an age- dependent susceptibility of white matter to ischemia/reperfusion during CPB, iii) Age- dependent susceptibility is a consequence of selective vulnerability of specific oligodendrocyte precursor cells which will be defined, iv) Specific bypass strategies and anti-inflammatory adjunctive treatment can reduce the risk of WMI associated with CPB. The models that will be used will be a piglet model of CPB with survival to 3 and 24 days. End points will include behavioral studies, MRI assessment of white matter and detailed histological assessment including identification of oligodendrocyte cell lineage using piglet appropriate antibodies that we have recently identified. The second model is a mouse brain slice model using a custom built perfusion chamber that allows manipulation of conditions including cytokine levels, temperature, pH, oxygen and glucose levels, thereby recreating the stresses of CPB. This model will allow investigation of transgenic mice specifically developed for the study of white matter. The goal of this project is improve protection of developing white matter during pediatric cardiac surgery and to reduce the incidence of deficits in motor skills in children undergoing surgery for congenital heart disease.

描述（由申请人提供）：先天性心脏病手术后儿童发育的前瞻性临床试验和回顾性临床研究都证明，运动技能的预后比认知能力更糟糕。这一发现与心脏手术后新生儿和婴儿中使用磁共振成像（MRI）的几项最近的研究一致，这些研究记录了白质损伤证据（WMI）。假定的新生儿对WMI的选择性脆弱性导致一些人暗示，尽管有许多优势，但仍应在新生儿期间避免纠正手术。 WMI在新生儿中的可疑病因包括对心肺旁路（CPB）有害影响的独特敏感性，包括夸张的全身性炎症反应以及缺血/再灌注的风险。旁路策略包括快速冷却，极端的血液稀释和严重的碱度以及某些循环停滞技术，以严重限制氧气输送。由于超低的出生体重早产婴儿也容易受到运动发育的不足，并且还证明了MRI的WMI证据，因此非常关注着明显的关注。免疫组织化学方法和特异性开发的转基因小鼠允许鉴定细胞谱系，从而导致成熟的少突胶质细胞，这些少突胶质细胞负责髓磷脂的铺设。拟议的研究将检验以下假设：i）白质对CPB的炎症作用有一种依赖性的敏感性，ii）ii）白质对白质对CPB缺血/再灌注的年龄易感性在CPB，III中，III）年龄依赖性依赖性依赖性的特定型号是特定的特定型号的特定型号，而特定的弱点是特定的弱点，并且是特定的Oligodersor oligodersor oligoderiv oiliv oiliv）抗炎辅助治疗可以降低与CPB相关的WMI的风险。将使用的模型将是CPB的小猪模型，生存期至3和24天。终点将包括行为研究，对白质的MRI评估以及详细的组织学评估，包括使用我们最近已经确定的适当抗体来鉴定少突胶质细胞谱系。第二个模型是使用自定义的灌注室的小鼠脑切片模型，该模型允许操纵包括细胞因子水平，温度，pH值，氧气和葡萄糖水平的状况，从而重现CPB的应力。该模型将允许研究专门为白质研究而开发的转基因小鼠。该项目的目的是改善对小儿心脏手术期间白质的保护，并减少正在接受先天性心脏病手术的儿童运动技能缺陷的发生率。