Metabolic basis for oligo-vascular interactions in white matter development and injury

Neonatal white matter injury (NWMI) is a major cause of motor and cognitive abnormalities in infants born pre- term, as well as in term births with complications such as intrauterine growth restriction, placental abruption, and birth asphyxia. Cerebral hypoxia and altered fetal circulation cause myelination defects in these conditions. However, the underlying mechanisms that disrupt the myelination by oligodendrocytes in hypoxic-ischemia are not completely clear. Myelination is a metabolically demanding process, requiring adequate vascularization, blood flow and oxygen content, all which can be compromised in pre-term or term birth with complications leading to NWMI. The central objective of this proposal is to understand how oligodendroglia obtain metabolic support from the white matter vasculature in normal development, and how this process is affected in neonatal hypoxic- ischemic brain injury. We recently demonstrated that oligodendroglial progenitor cells (OPC), an early precursor of the myelin forming oligodendrocytes, orchestrate white matter angiogenesis. This project aims to uncover a previously undefined mechanism involving endothelial-apelin signaling, which metabolically supports white matter vascularization and myelination. We propose to use various genetic and pharmacological strategies to (1) dissect out the mechanism of how OPCs regulate endothelial-apelin signaling in normal development and after neonatal hypoxic-ischemic (H-I) injury. (2) Next, understand how this process regulates cerebrovascular- tone, glucose uptake and vascularization in normal development and after neonatal H-I injury. (3) Finally, we will determine how brain wide hypoglycemia affects myelination and oligodendrocyte-metabolic pathways in normal development and after neonatal H-I injury. Together, these three aims will explore the metabolic crosstalk between oligodendroglia and endothelium and can provide insights into the protective mechanisms against disturbances in cerebral blood flow and oxygen delivery. The knowledge gained from these studies could result in potential therapeutics that might benefit the long-term neurodevelopment of children affected by neonatal hypoxic-ischemic brain injury, pediatric stroke, preterm birth, and other significant birth complications targeting the developing brain. Project Number: 1R01NS144584-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: Manideep Chavali | Institution: OREGON HEALTH & SCIENCE UNIVERSITY, PORTLAND, OR | Award Amount: $536,121 | Activity Code: R01 | Study Section: Developmental Brain Disorders Study Section[DBD] View on NIH RePORTER: https://reporter.nih.gov/project-details/11365536