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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

基本信息

批准号：
9285872
负责人：
RICHARD A JONAS
金额：
$ 76.24万
依托单位：
CHILDREN'S RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
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/9285872
关键词：
Animals Axon Birth Brain Brain Hypoxia Brain Hypoxia-Ischemia Brain Injuries Brain Ischemia 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 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 Deficit 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 Stem cells Techniques Technology Testing Time cell motility congenital heart disorder effective therapy experimental study implantation improved in utero in vivo innovation insight iron oxide migration mouse model myelination nanoparticle neonate novel novel strategies oligodendrocyte progenitor postnatal premature neonates prenatal progenitor public health relevance relating to nervous system stem subventricular zone white matter white matter injury

项目摘要

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.