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 #
5R01NS075156-04
Application #
8693034
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
2014-08-01
Budget End
2015-07-31
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Henry Ford Health System
Department
Type
DUNS #
City
Detroit
State
MI
Country
United States
Zip Code
48202
Xin, Hongqi; Katakowski, Mark; Wang, Fengjie et al. (2017) MicroRNA cluster miR-17-92 Cluster in Exosomes Enhance Neuroplasticity and Functional Recovery After Stroke in Rats. Stroke 48:747-753
Xin, Hongqi; Wang, Fengjie; Li, Yanfeng et al. (2017) Secondary Release of Exosomes From Astrocytes Contributes to the Increase in Neural Plasticity and Improvement of Functional Recovery After Stroke in Rats Treated With Exosomes Harvested From MicroRNA 133b-Overexpressing Multipotent Mesenchymal Stromal Ce Cell Transplant 26:243-257
Liu, Xian Shuang; Chopp, Michael; Pan, Wan Long et al. (2017) MicroRNA-146a Promotes Oligodendrogenesis in Stroke. Mol Neurobiol 54:227-237
Zhang, Yi; Chopp, Michael; Liu, Xian Shuang et al. (2017) Exosomes Derived from Mesenchymal Stromal Cells Promote Axonal Growth of Cortical Neurons. Mol Neurobiol 54:2659-2673
Kassis, Haifa; Shehadah, Amjad; Chopp, Michael et al. (2017) Epigenetics in Stroke Recovery. Genes (Basel) 8:
Liu, Xian Shuang; Fan, Baoyan; Szalad, Alexandra et al. (2017) MicroRNA-146a Mimics Reduce the Peripheral Neuropathy in Type 2 Diabetic Mice. Diabetes 66:3111-3121
Jiang, Quan; Zhang, Li; Ding, Guangliang et al. (2017) Impairment of the glymphatic system after diabetes. J Cereb Blood Flow Metab 37:1326-1337
Liu, Xian Shuang; Fan, Bao Yan; Pan, Wan Long et al. (2017) Identification of miRNomes associated with adult neurogenesis after stroke using Argonaute 2-based RNA sequencing. RNA Biol 14:488-499
Jia, Longfei; Wang, Lei; Chopp, Michael et al. (2017) MiR-29c/PRKCI Regulates Axonal Growth of Dorsal Root Ganglia Neurons Under Hyperglycemia. Mol Neurobiol :
Zhang, Zheng Gang; Chopp, Michael (2016) Exosomes in stroke pathogenesis and therapy. J Clin Invest 126:1190-7

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