MicroRNAs (miRNAs) regulate biological function of neural progenitor cells and oligodendrocyte progenitor cells (OPCs). Our preliminary data show that stroke substantially changed miRNA expression profiles in adult neural progenitor cells and oligodendrocytes. In this application, we propose to test the hypothesis that miRNAs in neural and OPCs play a pivotal role in mediating adult neurogenesis and oligodendrogenesis in the ischemic brain.
In Specific Aim 1, we will investigate the effect of inactive miRNA processes in neural progenitor cells and OPCs on stroke-induced neurogenesis and oligodendrogenesis by conditional and inducible Dicer ablation in Ascl1 lineage cells (Ascl1-CreTM/Dicerflox/flox).
In Specific Aim 2, we will investigate whether the sonic hedgehog (Shh) signaling pathway interacts with the miR-17-92 cluster to increase neurogenesis and oligodendrogenesis.
In Specific Aim 3, we will investigate the effect of the miR17-92 cluster on biological function of neural and oligodendrocyte progenitor cells in the ischemic brain by deletion or overexpression of the miR17-92 cluster in neural progenitor cells and OPCs after stroke. These studies will provide novel insights into miRNAs in regulating stroke-induced neurogenesis and oligodendrogenesis, which could potentially lead to new therapies to amplify neurogenesis and oligodendrogenesis in injured brain.

Public Health Relevance

Neurogenesis and oligodendrogenesis are associated with functional recovery after stroke. Molecular mechanisms underlying generation of new neurons and oligodendrocytes in ischemic brain have not been fully understood. Our preliminary data suggest that MicroRNAs (miRNAs), short noncoding RNA molecules, could be essential components in mediating stroke-induced neurogenesis and oligodendrogenesis. In this application, we propose three experiments to investigate the role of miRNAs in regulating adult neurogenesis and oligodendrogenesis in the ischemic brain. We will first delete Dicer to inactive miRNA processes in neural progenitor cells and oligodendrocyte progenitor cells (OPCs) after stroke. We will then examine a linkage between the sonic hedgehog (Shh) signaling pathway and miR17-92 expression in mediating neurogenesis and oligodendrogenesis. Finally, we will ablate or overexpress the miR17-92 cluster in neural progenitor cells and OPCs. These studies will provide novel insights into miRNAs in regulating stroke-induced neurogenesis and oligodendrogenesis, which could potentially lead to new therapies to amplify neurogenesis and oligodendrogenesis in injured brain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS075156-03
Application #
8516125
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Bosetti, Francesca
Project Start
2011-09-15
Project End
2016-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
3
Fiscal Year
2013
Total Cost
$309,253
Indirect Cost
$98,159
Name
Henry Ford Health System
Department
Type
DUNS #
073134603
City
Detroit
State
MI
Country
United States
Zip Code
48202
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