Aberrations in oligodendrocyte development resulting from congenital heart disease and its surgical treatment

先天性心脏病引起的少突胶质细胞发育异常及其手术治疗

• 批准号: 9100912
• 负责人: RICHARD A JONAS
• 金额: $ 71.33万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9100912
• 关键词: Animals; Axon; Birth; Brain; Brain Hypoxia-Ischemia; Brain Injuries; Cardiac Surgery procedures; Cardiopulmonary Bypass; Cell Differentiation process; Cell Maturation; Cell Transplants; Cell physiology; Cells; Child; Clinical; Cognitive deficits; Complex; Decision Making; Development; Diffusion Magnetic Resonance Imaging; Family suidae; Generations; Growth; Health; Histology; Human; Hypoxia; Impairment; In Vitro; Incidence; Individual; Inflammatory; Label; Location; Low Birth Weight Infant; Magnetic Resonance Imaging; Measures; Methodology; Methods; Modeling; Monitor; Morbidity - disease rate; Motor; Myelin; Neonatal; Neurologic; Newborn Infant; Oligodendroglia; Operative Surgical Procedures; Outcome; Outcome Study; Patients; Perinatal; Perinatal Care; Play; Population; Prevention; Problem behavior; Publications; Reperfusion Therapy; Risk; Rodent; Rodent Model; Role; Secondary to; Source; Staging; Stem cells; Techniques; Technology; Testing; Time; Ventricular; base; cell motility; congenital heart disorder; effective therapy; implantation; improved; in utero; in vivo; innovation; insight; iron oxide; migration; mouse model; myelination; nanoparticle; neonate; novel; novel strategies; postnatal; premature neonates; prenatal; progenitor; relating to nervous system; research study; stem; white matter; white matter injury

 DESCRIPTION (provided by applicant): Delayed brain development and white matter (WM) injury are common in neonates with congenital heart disease (CHD) at the time of birth. Both have been documented by clinical MRI studies. New WM injury is also common in these same individuals with CHD following neonatal cardiac surgery, most likely secondary to the deleterious effects of cardiopulmonary bypass (CPB). New WM injury is more likely to be seen in the immature brain resulting from CHD-induced in utero hypoxia. However, cellular mechanisms underlying delayed maturation and WM injury in CHD and effects of CPB on immature brain remain poorly understood. Insights into these mechanisms would allow prevention and/or development of effective treatment for neonatal WM injury in patients with CHD. Previous studies have documented that in the neonatal rodent brain hypoxia and ischemia alter generation and migration of oligodendrocyte progenitor cells (OPCs). Prolonged hypoxia also delays OPC differentiation in a mouse model leading to WM hypomyelination. WM hypomyelination is one component of a clinically-applied scale for brain immaturity. Therefore, we will test the following hypotheses: i) Impairment of OPC generation and differentiation in the WM due to preoperative hypoxia results in WM hypomyelination and brain immaturity; ii) Both the inflammatory effects of CPB as well as the reperfusion and reoxygenation of circulatory arrest exacerbate the impaired generation and delayed OPC migration and maturation. The first model that will be used will be a piglet hypoxia model. Immature development of the porcine brain in this experimental paradigm is very similar to that observed in newborns with CHD. The impact of CPB on the immature brain will be investigated with a combined paradigm using piglets exposed to both hypoxia and CPB. To analyze OPC maturation in the porcine brain, we have generated OPCs derived from porcine stem/progenitor cells. Proliferation of OPCs will be measured using immunohistochemical methods. OPC migration will be continuously monitored by novel cell tracking MRI techniques using superparamagnetic iron oxide labeling in vivo. Development from OPCs to mature oligodendrocytes will be defined by fluorescent marker histology. Microstructural maturation of WM will be analyzed by serial volumetric analysis and diffusion tensor imaging. Finally correlation between microstructural maturation and brain immaturity will be defined. The proposed studies will define crucial cellular mechanisms underlying the causes of brain immaturity and WM injury in the neonate with CHD. The findings will assist decision-making regarding optimal timing and techniques of surgery. The proposed studies have the potential to identify and assess novel strategies to treat brain immaturity and WM injury, and define new standards of perinatal care in the patient with CHD. The resulting improved neurodevelopmental outcomes would be of enormous benefit to those individuals with CHD.

 描述（由适用提供）：出生时先天性心脏病（CHD）的脑发育和白质（WM）损伤很常见。两者都通过临床MRI研究记录。新的WM损伤在新生儿心脏手术后的同一冠心病患者中也很常见，最有可能是心肺旁路（CPB）的有害作用。由于子宫缺氧引起的CHD引起的冠心病，更有可能在未成熟的大脑中看到新的WM损伤。然而，冠心病中延迟成熟和WM损伤的细胞机制以及CPB对不成熟大脑的影响仍然很少了解。对这些机制的洞察力将允许预防和/或开发有效的CHD患者新生儿WM损伤。先前的研究表明，在新生儿啮齿动物脑缺氧和缺血中，少突胶质细胞祖细胞（OPC）的产生和迁移改变了。长时间的缺氧还延迟了导致WM低髓系的小鼠模型中的OPC分化。 WM低切除率是临床应用量表的大脑不成熟量表的一部分。因此，我们将检验以下假设：i）由于术前缺氧导致WM缺血和大脑不成熟，因此WM的OPC产生和WM中的分化受损； ii）CPB的炎症作用以及电路停滞的再灌注和再融合加剧了发电障碍和OPC迁移和成熟的延迟。将使用的第一个模型将是小猪缺氧模型。在这种实验范式中，猪大脑的不成熟发育与在新生儿中观察到的冠心病非常相似。 CPB对未成熟大脑的影响将使用暴露于缺氧和CPB的仔猪的合并范式研究。分析猪大脑中的OPC成熟，我们已经产生了源自猪干/祖细胞的OPC。 OPC的增殖将使用免疫组织化学方法测量。 OPC迁移将通过在体内使用氧化铁标记的新细胞跟踪MRI技术来连续监测。从OPC到成熟的少突胶质细胞的发展将由荧光标记组织学定义。 WM的微观结构成熟将通过串行体积分析和扩散张量成像进行分析。最终，将定义微观结构成熟与脑不成熟之间的相关性。拟议的研究将定义至关重要的细胞机制，这是新生儿用CHD造成脑不成熟和WM损伤的原因。这些发现将有助于有关手术最佳时机和技术的决策。拟议的研究具有识别和评估治疗大脑不成熟和WM损伤的新型策略，并确定CHD患者的围产期护理的新标准。由此产生的改善的神经发育结果将对那些冠心病患者带来巨大的好处。