The retinal photoreceptors are the light-sensing cells that convert complex external visual stimuli to electrical and chemical signals. Degeneration of photoreceptors is the end point of the commonest causes of irreversible blindness including age-related macular degeneration and retinitis pigmentosa, affecting over 50 million people world-wide. In non-mammalian vertebrates such as fish, after retinal injury, resident Muller glia cells in the retina can proliferate, and differentiate into all retinal cell types including photoreceptors and restore visual functions. However, this regenerative potential is almost non-existent in mammals, with only very few new neurons generated after damage. We propose to develop and apply a high throughput screening to identify small molecules that will enhance Muller glia cells reprogramming and differentiation into retinal neurons in mammals, in vitro and in vivo. Identification, optimization, and characterizations of chemical tools for Muller cells reprogramming and differentiation will provide new avenues in developing cell-based therapy as well as conventional small molecule therapeutics for regenerative medicine, and facilitate new understanding of the transdifferentiation mechanisms. Our proposed research will facilitate the development of therapies to restore visual functions that have been lost in human patients with severe blindness.

Public Health Relevance

Identification, optimization, and characterizations of chemical tools for Muller cells reprogramming and differentiation will provide new avenues in developing cell-based therapy as well as conventional small molecule therapeutics for regenerative medicine, and facilitate new understanding of the transdifferentiation mechanisms. Our proposed research will facilitate the development of therapies to restore visual functions that have been lost in human patients with severe blindness.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY021374-03
Application #
8327245
Study Section
Special Emphasis Panel (ZRG1-BCMB-A (51))
Program Officer
Greenwell, Thomas
Project Start
2010-09-30
Project End
2015-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
3
Fiscal Year
2012
Total Cost
$831,267
Indirect Cost
$128,718
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Gou, Maling; Qu, Xin; Zhu, Wei et al. (2014) Bio-inspired detoxification using 3D-printed hydrogel nanocomposites. Nat Commun 5:3774
Luo, Jing; Baranov, Petr; Patel, Sherrina et al. (2014) Human retinal progenitor cell transplantation preserves vision. J Biol Chem 289:6362-71
Zhao, Jack Jiagang; Ouyang, Hong; Luo, Jing et al. (2014) Induction of retinal progenitors and neurons from mammalian Müller glia under defined conditions. J Biol Chem 289:11945-51
Ouyang, Hong; Xue, Yuanchao; Lin, Ying et al. (2014) WNT7A and PAX6 define corneal epithelium homeostasis and pathogenesis. Nature 511:358-61
Wang, Feng; Wang, Hui; Tuan, Han-Fang et al. (2014) Next generation sequencing-based molecular diagnosis of retinitis pigmentosa: identification of a novel genotype-phenotype correlation and clinical refinements. Hum Genet 133:331-45
Hannum, Gregory; Guinney, Justin; Zhao, Ling et al. (2013) Genome-wide methylation profiles reveal quantitative views of human aging rates. Mol Cell 49:359-67
Luo, Jing; Zhao, Ling; Chen, Aaron Yun et al. (2013) TCF7L2 variation and proliferative diabetic retinopathy. Diabetes 62:2613-7
Du, Hongjun; Sun, Xufang; Guma, Monica et al. (2013) JNK inhibition reduces apoptosis and neovascularization in a murine model of age-related macular degeneration. Proc Natl Acad Sci U S A 110:2377-82
Zhao, Jiagang; Sun, Woong; Cho, Hyo Min et al. (2013) Integration and long distance axonal regeneration in the central nervous system from transplanted primitive neural stem cells. J Biol Chem 288:164-8
Zhao, L; Grob, S; Avery, R et al. (2013) Common variant in VEGFA and response to anti-VEGF therapy for neovascular age-related macular degeneration. Curr Mol Med 13:929-34

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