MicroRNAs and Perinatal Hypoxia-Ischemia

Project: Research project

Project Details

Description

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 living like 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 near absence of therapies for babies at risk; at present, there is
only antenatal magnesium. Recognition of microRNAs as important regulators of gene expression
make 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 on 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 hypoxia-ischemia, (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”.
StatusFinished
Effective start/end date4/1/149/30/15

Funding

  • Ann & Robert H. Lurie Children's Hospital of Chicago (#925467-NU)

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