White matter injury associated with prematurity is currently the leading cause of cerebral palsy. Oligodendrocytes, the myelinating cells of the brain, are thought to be vulnerable to hypoxic damage in very preterm human neonates (24-32 weeks gestational age). Oxygenation in such infants may be severely disrupted due to either hypoxia (e.g., from respiratory distress, hypotension) or relative hyperoxia (e.g., PaO2 ~60-80 in NICU versus PaO2 ~30-40 in utero.) Elucidating the mechanisms that underlie the response of mature and immature oligodendrocytes to hypoxia will thus greatly advance our understanding of developmental white matter injury. This proposal details a 3 year plan for doctoral dissertation research under the mentorship of Dr. David Rowitch. The fellow will investigate the role of hypoxia and Hypoxia Inducible Factors, the principle transcriptional mediators of the cellular hypoxia response, in normal oligodendrocyte development and a mouse model of chronic neonatal hypoxic brain injury. The fellow will utilize and further develop his expertise in histology, oligodendrocyte cell culture techniques, mouse genetics, and neurostereology to accomplish these goals through the following specific aims: 1.) To determine the regulation of wild type oligodendrocyte lineage proliferation and differentiation by hypoxia in vitro and in vivo;2.) To determine whether Hypoxia Inducible Factor (HIF) signaling is critical for oligodendrocyte development;3.) To determine the contribution of Hypoxia Inducible Factor signaling to chronic neonatal hypoxic brain injury. The expertise of Dr. Rowitch in white matter injury, glial development, and neonatology, coupled with the advice of our collaborator Dr. Emin Maltepe an expert on HIF biology, will provide the intellectual and technical guidance necessary to ensure successful completion of these aims. The research plan proposed here along with the fellow's choice of mentorship will provide excellent training towards the fellow's goal of an academic career in developmental neuroscience and translational brain injury research.
This project explores the mechanisms of a form brain injury associated with premature birth called developmental white matter injury or perventricular leukomalacia, which is the leading cause of new cases of cerebral palsy. This injury is caused by the death and impaired development of a type of brain cell called oligodendrocytes which insulate and provide support to axons (the part of the neuron that carries nervous impulses). Because decreased levels of oxygen to the brain are a major cause of this injury, we propose to study the response of oligodendrocytes in the developing brain to abnormally low oxygen levels.
|Yuen, Tracy J; Silbereis, John C; Griveau, Amelie et al. (2014) Oligodendrocyte-encoded HIF function couples postnatal myelination and white matter angiogenesis. Cell 158:383-96|
|Silbereis, John C; Nobuta, Hiroko; Tsai, Hui-Hsin et al. (2014) Olig1 function is required to repress dlx1/2 and interneuron production in Mammalian brain. Neuron 81:574-87|