Neural stem cells residing in specialized niches in the adult mammalian brain may represent a large pool of cells that can be stimulated for brain repair. Adult neural stem cells continuously generate new neurons that functionally integrate into neural circuits. Defining the molecular events that underly stem cell self-renewal and differentiation are essential steps towards harnessing the endogenous stem cells and progenitors for brain repair. While recent progress has been made in identifying transcriptional pathways regulating these processes, post-transcriptional regulatory mechanisms are almost completely unknown. MicroRNAs are a novel class of small non-coding RNAs that largely act by repressing translation. We hypothesize that miRNAs are key mediators of stem cell biology and cell fate decisions and act in concert with transcriptional regulators to control adult neural stem cell self-renewal and differentiation. We propose here to 1) characterize the functional role of 3 miRNAs we have identified in the adult neural stem cell lineage. We will use retroviruses to ectopically over-express and knock down these miRNAs in cultured neural stem cells to examine their functional role in stem cell self-renewal and differentiation. We will determine the functional consequences for adult neurogenesis in vivo by retroviral over-expression and knock down of these miRNAs. 2) We will identify the physiological targets of these miRNAs, which will yield important insight into the networks regulated by miRNAs. 3) We will clone and characterize specific libraries of miRNAs for each cell stage in the lineage of adult neurogenesis. These studies will yield key insights into the function of miRNAs in stem cells for adult neurogenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
3R01NS053884-03S1
Application #
7869571
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Owens, David F
Project Start
2006-07-01
Project End
2011-08-31
Budget Start
2009-09-01
Budget End
2011-08-31
Support Year
3
Fiscal Year
2009
Total Cost
$151,946
Indirect Cost
Name
Columbia University (N.Y.)
Department
Pathology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
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Codega, Paolo; Silva-Vargas, Violeta; Paul, Alex et al. (2014) Prospective identification and purification of quiescent adult neural stem cells from their in vivo niche. Neuron 82:545-59
Pastrana, Erika; Silva-Vargas, Violeta; Doetsch, Fiona (2011) Eyes wide open: a critical review of sphere-formation as an assay for stem cells. Cell Stem Cell 8:486-98
Cheng, Li-Chun; Pastrana, Erika; Tavazoie, Masoud et al. (2009) miR-124 regulates adult neurogenesis in the subventricular zone stem cell niche. Nat Neurosci 12:399-408
Pastrana, Erika; Cheng, Li-Chun; Doetsch, Fiona (2009) Simultaneous prospective purification of adult subventricular zone neural stem cells and their progeny. Proc Natl Acad Sci U S A 106:6387-92