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: 10038610
• 负责人: Manideep Chavali
• 金额: $ 10.52万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 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 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10038610
• 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; Structure; 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，仅在美国每年就有大约4万新生儿受到影响。虽然手术创新极大地提高了冠心病儿童的生存率，但幸存者的神经认知能力差是一个严重的问题，引发了关于慢性低氧血症对大脑发育影响的问题。新生儿白质损伤（WMI）包括缺氧缺血性脑病和脑室周围白质软化症是最常见的导致不良神经发育结果的原因，如冠心病新生儿脑瘫。白质由轴突组成，轴突由髓鞘少突胶质细胞隔离。因为髓磷脂的形成是一个需要代谢的过程，它需要通过白质束的血管网络提供充足的血流量、营养和氧气。发育过程中的心脏结构缺陷可导致冠心病流出道错位，损害胎儿循环和脑氧输送，导致髓鞘形成缺陷和WMI。在我的博士后研究期间，我有一个惊人的发现，OPC密度是白质血管生成的直接调节器。利用一种新的小鼠冠心病模型，模拟了人类冠心病中观察到的结构性右至左分流缺陷（TGA）、双出口右心室和室间隔缺陷，我也发现了这种情况下新生儿白质的异常血管化。本研究的目的是了解OPCs调节白质血管发育的机制，以及由此产生的血管网络如何提供必要的代谢支持，以保护慢性低氧血症的新生儿大脑，这是典型的冠心病。在K99期，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小鼠冠心病模型中的白质OPC-内皮细胞相互作用和潜在的分子途径，并在从人类缺氧缺血性脑病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，我将结合小鼠遗传学和缺氧损伤模型来了解这些通路的破坏如何影响白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特异性信号网络的改变。这项工作将在博士的指导下进行。David Rowitch和Stephen Fancy是研究白质发育、新生儿白质损伤和神经胶质血管串扰的领军人物。博士将提供补充指导。Eric Huang， Patrick Mcquillen和Alma Burlingame分别是神经病理学，冠心病神经发育和基于质谱的蛋白质组学方法的专家。在独立的R00期，我将研究白质血管发育的中断或异常血流是如何导致少突胶质细胞代谢功能障碍的，并探索小分子候选物来靶向受影响的信号网络，以挽救这些低氧条件下所见的髓鞘形成缺陷。这些努力将提供关于发育中的白质中少突胶质细胞和血管网络之间双向串扰的机制见解，以及它们如何在冠心病、早产和小儿中风中观察到的新生儿脑损伤中发生改变。