Oligo-Vascular Crosstalk in the Developing Brain: Implications For White Matter Injury In Congenital Heart Disease

发育中大脑中的寡血管串扰：对先天性心脏病白质损伤的影响

• 批准号: 10619110
• 负责人: Manideep Chavali
• 金额: $ 24.87万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10619110
• 关键词: Affect; Attenuated; Autopsy; Axon; Behavioral; Birth; Blood Circulation; Blood Vessels; Blood flow; Brain; Brain Injuries; Cardiac; Cell Communication; Cell Density; Cell Lineage; Cells; Cerebral Palsy; Cerebrum; Child; Childhood stroke; Chronic; Cognitive; Data Set; Defect; Development; Disease; Double Outlet Right Ventricle; Electron Microscopy; Endothelial Cells; Endothelium; Genes; Goals; Human; Hypoxemia; Hypoxia; Image; Immunohistochemistry; In Situ Hybridization; Infant; Injury; Knockout Mice; Lead; Left; Ligands; Light; Mass Spectrum Analysis; Mentors; Mentorship; Metabolic; Metabolic dysfunction; Metabolic stress; Metabolism; Modeling; Molecular; Myelin; Neonatal; Neonatal Brain Injury; Neurocognitive; Neuroglia; Nutrient; Oligodendroglia; Oligonucleotides; Operative Surgical Procedures; Outcome; Oxidative Stress Pathway; Oxygen; Pathway interactions; Periventricular Leukomalacia; Pharmacology; Phase; Premature Birth; Process; Proteomics; Role; Shunt Device; Signal Transduction; Specimen; Stearoyl-CoA Desaturase; Structural defect; Supporting Cell; Survivors; Techniques; Time; Training; Transposition of Great Vessels; United States; Up-Regulation; Vascular Endothelial Growth Factors; Vascularization; Ventricular Septal Defects; Work; angiogenesis; base; brain tissue; candidate marker; conditional knockout; congenital heart disorder; endothelial stem cell; experimental study; fetal; human disease; imaging approach; improved; innovation; insight; malformation; mouse genetics; mouse model; myelination; myocardial hypoxia; neonatal brain; neonatal hypoxic-ischemic brain injury; neonate; neurodevelopment; neuropathology; new therapeutic target; novel; oligodendrocyte precursor; oligodendrocyte progenitor; programs; resilience; skills; small molecule; stem cells; tool; transcriptome sequencing; transcriptomics; white matter; white matter injury

Congenital heart disease (CHD) is a common malformation that affects about 40,000 births each year in the United States alone. While surgical innovations have dramatically improved survival in children with CHD, the poor neurocognitive outcome of survivors is a grave concern, raising questions about effects of chronic hypoxemia on brain development. Neonatal white-matter injuries (WMI) including hypoxic-ischemic encephalopathy and periventricular leukomalacia are the most common causes of adverse neurodevelopmental outcomes such as cerebral palsy in neonates with CHD. The white matter comprises axons that are insulated by myelinating oligodendrocytes. Because, myelin formation is a metabolically demanding process, it requires adequate blood flow, nutrient and oxygen delivery supplied through vascular network in the white matter tracts. Cardiac structural defects during development lead to outflow tract misalignment in CHD and can compromise the fetal circulation and cerebral oxygen delivery resulting in myelination deficits and WMI. During my postdoctoral studies, I made a striking discovery that OPC density is a direct regulator of white matter angiogenesis. Using a novel mouse model of CHD that mimics structural right to left shunt defects of transposition of great arteries (TGA), double outlet right ventricle and ventricular septal defects observed in human CHD, I also uncovered abnormal vascularization of neonatal white matter in this condition. The goal of this proposal is to understand mechanisms by which OPCs regulate white matter vascular development and how the resulting vascular network provides essential metabolic support to protect the neonatal brain subject to chronic hypoxemia, as is typical in CHD. During the K99 phase, I propose to characterize white matter OPC- endothelial cell interactions and the underlying molecular pathways in our mouse model of CHD using advanced spatial transcriptomics and live imaging approaches and further validate them in postmortem brain tissue obtained from human cases of hypoxic ischemic encephalopathy to understand their relevance to human disease. I will next combine mouse genetics and hypoxic injury models to understand how disruption in these pathways impact white matter vascularization and myelination. Using cutting-edge proteomics technique, I will further elucidate the downstream oligodendroglial specific-signaling network alterations in these conditions. This work will be carried out under the mentorship of Drs. David Rowitch and Stephen Fancy, leaders in white matter development, neonatal white matter injury and glia-vascular cross talk. Complementary mentorship will be provided by Drs. Eric Huang, Patrick Mcquillen and Alma Burlingame experts in neuropathology, neurodevelopment in CHD and mass spectrometry-based proteomics approaches respectively. During the independent R00 phase, I will investigate how disruption in white matter vascular development or abnormal blood flow cause metabolic dysfunction in oligodendrocytes and explore small molecule candidates to target the affected signaling networks to rescue the myelination deficits seen in these hypoxemic conditions. These efforts will provide mechanistic insights into a bidirectional crosstalk between oligodendroglial cells and vascular network in the developing white matter, and how they are altered in neonatal brain injury seen in CHD, Preterm Birth and Pediatric Stroke.

先天性心脏病（CHD）是一种常见的畸形，仅在美国每年就影响约40，000名新生儿。虽然手术创新大大提高了CHD儿童的生存率，但幸存者的神经认知结果较差，这是一个严重的问题，引起了人们对慢性低氧血症对大脑发育影响的质疑。新生儿脑白质损伤（EEG），包括缺氧缺血性脑病和脑室周围白质软化症是最常见的不良神经发育结果的原因，如脑性瘫痪的新生儿CHD。白色物质包括被髓鞘化少突胶质细胞绝缘的轴突。因为髓磷脂的形成是一个代谢要求很高的过程，它需要通过白色物质束中的血管网提供足够的血流、营养和氧气。发育过程中的心脏结构缺陷导致CHD流出道错位，并可能损害胎儿循环和脑氧输送，导致髓鞘形成缺陷和脑缺血。在我的博士后研究中，我有一个惊人的发现，OPC密度是白色血管生成的直接调节因子。使用一种新的小鼠CHD模型，模仿结构性右向左分流缺陷的大动脉转位（TGA），双出口右心室和室间隔缺损观察人类CHD，我也发现异常血管新生儿白色物质在这种情况下。本提案的目的是了解OPCs调节白色血管发育的机制，以及由此产生的血管网络如何提供必要的代谢支持，以保护患有慢性低氧血症的新生儿大脑，这在CHD中是典型的。在K99阶段，我建议使用先进的空间转录组学和实时成像方法来表征我们的CHD小鼠模型中的白色物质OPC-内皮细胞相互作用和潜在的分子途径，并在从缺氧缺血性脑病的人类病例中获得的死后脑组织中进一步验证它们，以了解它们与人类疾病的相关性。接下来，我将结合联合收割机小鼠遗传学和缺氧损伤模型，以了解这些通路的中断如何影响白色物质血管化和髓鞘形成。利用尖端的蛋白质组学技术，我将进一步阐明在这些条件下下游少突胶质细胞特异性信号网络的改变。这项工作将在大卫罗维奇和斯蒂芬范西博士的指导下进行，他们是白色物质发育、新生儿白色物质损伤和神经胶质血管串扰的领导者。Eric Huang博士、帕特里克Mcquillen博士和阿尔马Burlingame博士将分别在神经病理学、CHD神经发育和基于质谱的蛋白质组学方法方面提供补充指导。在独立的R 00阶段，我将调查如何破坏白色物质血管发育或异常血流导致少突胶质细胞代谢功能障碍，并探索小分子候选人，以针对受影响的信号网络，以挽救髓鞘形成缺陷，在这些低氧条件下看到。这些努力将提供机制的见解少突胶质细胞和血管网络之间的双向串扰在发展中的白色物质，以及它们如何改变在新生儿脑损伤中看到的冠心病，早产和儿科中风。