Diffuse white matter damage, a type of brain injury, commonly occurs with premature birth and is a leading cause of cerebral palsy and neurodevelopmental disorders. This type of brain injury is often caused by hypoxia due to immature lung development. Accumulating evidence from both postmortem human tissue and rodent models suggests delay of glial maturation is a major underlying cause of hypoxia-induced structural and functional neurological abnormalities. In particular, neonatal hypoxia causes delayed maturation of oligodendrocytes, the myelin-forming glia of the central nervous system (CNS), and results in myelin defects and motor and cognitive abnormalities. Human infants typically undergo extensive glial maturation and myelination during late prenatal and early postnatal life, when nutrition can be supplied solely by the mother. We have an incomplete understanding of maternally-derived factors that contribute to normal CNS myelination and which could be safely administered to infants to promote recovery from white matter injury. The goal of this research is to understand the role of the natural sugar alcohol myo-inositol in regulating signaling pathways that are essential for normal developmental myelination, and to determine whether supplementation of myo-inositol can promote recovery from white matter injury caused by chronic neonatal hypoxia. The central hypothesis is that myo-inositol activates phosphoinositide signaling pathways that promote oligodendrocyte myelination during development and in white matter injury. We will test this hypothesis in gain- and loss-of-function studies using in vitro and in vivo rodent models of normal development and chronic neonatal hypoxia.
Aim 1 will test whether oligodendrocyte uptake of myo-inositol drives myelin wrapping during development by modulating oligodendrocyte phosphoinositide levels.
Aim 2 will test whether myo-inositol rescues myelin defects and promotes functional recovery in chronic neonatal hypoxia by acting directly on oligodendrocytes. Upon completion these studies will have important implications both for understanding basic oligodendrocyte biology as well as for potential therapeutics for neonatal white matter injury. In order to conduct these studies, I will learn electron microscopy, mass spectrometry, and CRISPR-based gene editing under the guidance of my sponsor, Dr. Chan. I will also receive further training in critical career development skills such as presentations, scientific writing, and grantsmanship from Dr. Chan and by participating in UCSF seminars. I am confident that completion of the research goals described here, the mentorship I receive from Dr. Chan, and the rigorous research environment at UCSF will enable me to achieve my long-term goal of becoming a tenure-track independent investigator in academia.
Newborn brain injury is a highly prevalent complication of preterm birth and a leading cause of cerebral palsy and neurodevelopmental disorders. This proposal will use rodent models to investigate how the naturally- occurring nutrient myo-inositol regulates white matter brain development and whether myo-inositol can promote recovery from newborn brain injury. These studies may provide insight into possible therapeutic targets for treatment or prevention of cognitive and motor deficits associated with newborn brain injury.
