DESCRIPTION (provided by applicant): Our overarching goal is to understand developmental brain disorders that result from birth early in the last trimester of pregnancy, especially the adaptive response to injury by oligodendroglial progenitors cells, those cells that are abundant during this time period and differentiate into cells that form white matter. The clinical consequence of white matter injury within the developing brain, as often occurs when babies are born preterm and at low birth weight, is cerebral palsy. This disease is characterized by a lifelong abnormality of motor control that results in spasticity, making activities of daily livinglike feeding oneself or walking difficult. Whereas the association of white matter injury with hypoxia-ischemia is well documented, the mechanisms underlying decreased white matter are poorly understood. We and others have shown that hypoxia-ischemia induces an increase in oligodendroglial progenitors yet a paucity of white matter. Reflective of our poor understanding of the disease is the absence of specific therapies for babies at risk. Recognition of microRNAs as important regulators of gene expression makes them prime targets for the development of new therapeutic interventions. Presently, our understanding of microRNA regulation of oligodendrocyte fate commitment and differentiation is rudimentary. Our preliminary data supports a hypothesis that microRNAs regulate the response of oligodendroglial progenitors to hypoxia-ischemia. We will build upon our preliminary data to mechanistically decipher how microRNAs regulate oligodendroglial development in response to injury. Through our studies we seek to explore previously unknown pathways in the oligodendroglial response to perinatal hypoxia-ischemia. Our proposal is unique, because (a) we focus on novel pathways of gene regulation that have not been evaluated in oligodendroglial lineage cells within the context of perinatal hypoxiaischemia, (b) we utilize innovative mouse mutants to establish a "cause and effect" relationship, not just mere associations, and (c) we utilize cutting edge technology of diffusion tensor magnetic resonance imaging to evaluate our gain and loss of function experiments, a modality that is amenable to translation into clinical use. Our data will not only illuminate the molecular underpinnings of oligodendroglial adaptation to injury, but may also lay the foundation for novel therapies for preterm babies at risk for cerebral palsy, namely microRNA mimetics and "antagomiRs".

PUBLIC HEALTH RELEVANCE: Increasingly, as more preterm babies survive, the burden of cerebral palsy on individuals, their families and society grows. Our research is designed to elucidate the action of microRNAs in regulating the response of oligodendroglia to perinatal hypoxia-ischemia. Our experiments will broaden our understanding of myelination in the newborn brain, and therefore lead to true preventive and regenerative therapies.