Protection of Developing White Matter during Cardiac Surgery

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记录了运动技能比认知能力更差的结果。这一发现与最近在心脏手术后新生儿和婴儿中使用磁共振成像（MRI）的几项研究一致，这些研究记录了白色物质损伤（MRI）的证据。一个假定的新生儿选择性的脆弱性，使一些人建议，矫正手术应避免在新生儿时期，尽管它的许多优点。新生儿心脏病的可疑致病因素包括对心肺转流（CPB）有害影响的独特易感性，包括过度的全身炎症反应以及缺血/再灌注风险。包括快速冷却、极度血液稀释和重度碱性的旁路策略以及一些循环停止技术已被记录为严重限制氧气输送。由于超低出生体重早产儿在运动发育方面也易出现缺陷，并且通过MRI也显示出脑白质发育的证据，因此，对白色物质发育的了解已引起了相当大的关注。免疫组织化学方法和专门开发的转基因小鼠允许鉴定导致成熟少突胶质细胞的细胞谱系，所述少突胶质细胞负责髓鞘的沉积。拟议的研究将测试以下假设：i）白色物质对CPB的炎症效应具有年龄依赖性的易感性，ii）白色物质对CPB期间的缺血/再灌注具有年龄依赖性的易感性，iii）年龄依赖性的易感性是将被定义的特定少突胶质细胞前体细胞的选择性易损性的结果，iv）特定的旁路策略和抗炎性预防性治疗可降低CPB相关性心绞痛的风险。将使用的模型是存活期为3天和24天的CPB仔猪模型。终点将包括行为研究、白色物质的MRI评估和详细的组织学评估，包括使用我们最近鉴定的仔猪适当抗体鉴定少突胶质细胞谱系。第二个模型是使用定制灌注室的小鼠脑切片模型，该灌注室允许操纵包括细胞因子水平、温度、pH、氧气和葡萄糖水平在内的条件，从而再现CPB的应力。该模型将允许研究专为研究白色物质而开发的转基因小鼠。该项目的目标是在小儿心脏手术期间改善对发育中的白色物质的保护，并减少接受先天性心脏病手术的儿童运动技能缺陷的发生率。

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.