This application addresses broad Challenge Area (14: Stem Cells) and specific Challenge Topic (14-NS-101: Reverse Engineering Human Neurological Disease). Viral or plasmid introduction of a transcription factor quartet is proven a powerful strategy to trigger reprogramming somatic cells into induced pluripotent stem (iPS) cells without the need of embryos or eggs. However, genetic manipulation using transgenes represents a serious hurdle to the use of these iPS cells for therapeutic application. While reactivation of trangenes could lead to tumorigenesis, leaky expression of transgenes may inhibit iPS cell differentiation, increasing the risk of immature teratoma formation. One way to solve this problem is to identify small molecules that induce endogenous pluripotent regulators without gene transfer. Furthermore, generation of iPS cells using existing technology by viral transduction or plasmid transfection of the reprogramming factors is a process with very low efficiency. The main goal of this research is to derive transgene-free human iPS cells using small molecules and to identify compounds that enhance reprogramming efficiency. This study will lead to the development of new methods for the derivation ofpluripotent human stem cell lines with high efficiency and open a new avenue to generate patient- and disease-specific pluripotent stem cells. These chemically derived iPS cells will become valuable tools for developmental biology, drug discovery, and regenerative medicine.

Public Health Relevance

Chemical derivation of human iPS cells in virus-free and transgene-free means will open a new avenue to generate patient- and disease-specific pluripotent stem cells with high efficiency. These genetically unmodified iPS cells will be applicable in stem cell-based cell replacement therapies for the treatment of neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases, and brain injuries.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
NIH Challenge Grants and Partnerships Program (RC1)
Project #
1RC1NS068370-01
Application #
7822514
Study Section
Special Emphasis Panel (ZRG1-BDA-A (52))
Program Officer
Owens, David F
Project Start
2010-04-15
Project End
2013-09-30
Budget Start
2010-04-15
Budget End
2013-09-30
Support Year
1
Fiscal Year
2010
Total Cost
$1,000,000
Indirect Cost
Name
City of Hope/Beckman Research Institute
Department
Type
DUNS #
027176833
City
Duarte
State
CA
Country
United States
Zip Code
91010
Murai, Kiyohito; Qu, Qiuhao; Sun, GuoQiang et al. (2014) Nuclear receptor TLX stimulates hippocampal neurogenesis and enhances learning and memory in a transgenic mouse model. Proc Natl Acad Sci U S A 111:9115-20
Qu, Qiuhao; Sun, Guoqiang; Murai, Kiyohito et al. (2013) Wnt7a regulates multiple steps of neurogenesis. Mol Cell Biol 33:2551-9
Zhang, Run-Rui; Cui, Qing-Yan; Murai, Kiyohito et al. (2013) Tet1 regulates adult hippocampal neurogenesis and cognition. Cell Stem Cell 13:237-45
Zhao, Chunnian; Sun, GuoQiang; Ye, Peng et al. (2013) MicroRNA let-7d regulates the TLX/microRNA-9 cascade to control neural cell fate and neurogenesis. Sci Rep 3:1329
Asuelime, Grace E; Shi, Yanhong (2012) The little molecules that could: a story about microRNAs in neural stem cells and neurogenesis. Front Neurosci 6:176
Li, Wendong; Tian, E; Chen, Zhao-Xia et al. (2012) Identification of Oct4-activating compounds that enhance reprogramming efficiency. Proc Natl Acad Sci U S A 109:20853-8
Asuelime, Grace E; Shi, Yanhong (2012) A case of cellular alchemy: lineage reprogramming and its potential in regenerative medicine. J Mol Cell Biol 4:190-6
Lang, Ming-Fei; Shi, Yanhong (2012) Dynamic Roles of microRNAs in Neurogenesis. Front Neurosci 6:71
Lang, Ming-Fei; Yang, Su; Zhao, Chunnian et al. (2012) Genome-wide profiling identified a set of miRNAs that are differentially expressed in glioblastoma stem cells and normal neural stem cells. PLoS One 7:e36248
Li, Shengxiu; Sun, Guoqiang; Murai, Kiyohito et al. (2012) Characterization of TLX expression in neural stem cells and progenitor cells in adult brains. PLoS One 7:e43324

Showing the most recent 10 out of 14 publications