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

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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.