Kin-Sang (Anson) Cho, Ph.D.

Harvard Medical School

Instructor in Ophthalmology

Schepens Eye Research Institute of Massachusetts Eye and Ear

Investigator

Research Summary

Center/Research Area Affiliations

Biography

Dr. Cho studies the mechanisms of degeneration and regeneration of mammalian retina. His work can be categorized into three areas: 1) Elucidating the neuroptection mechanism of electrical stimulation on retinal neurons; 2) Investigating the mechanisms of disease progression of glaucoma therapeutic potential of stem cells on animal model of retinal degeneration; 3) Elucidating the key mechanism that promotes robust optic nerve regeneration. His long-term goal is to develop novel therapeutic strategies for retinal degenerative diseases, such as glaucoma and retinitis pigmentosa.

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Education

Ph.D., Neurobiology, University of Hong Kong

Postgraduate Training

Postdoctoral Fellowship, University of Hong Kong
Fellowship, Schepens Eye Research Institute of Mass. Eye and Ear

Honors

2005: Annual Best Paper Award Schepens Eye Research Institute of Mass. Eye and Ear
1998 Postdoctoral Fellowship, the University of Hong Kong
1997: The Hong Kong Brain Foundation Scholarship
1995: Asian Young Scientist Fellowship, International Brain Research Organization

His Story

The visual system has been used as a model to study central nervous system (CNS) regeneration. Dr. Cho's research has focused on why neurons in the CNS cannot re-grow in adult mammals. The expression pattern of Bcl-2 had been shown to correlate to the decline of intrinsic growth ability of retinal ganglion cells (CNS neurons inside retina) during development. In addition, he demonstrated that over-expressing Bcl-2 could maintain the intrinsic growth ability over growth-inhibitory substrates in culture.

Dr. Cho then explored if the over-expression of Bcl-2 is sufficient to support long-distance regeneration of the optic nerve from the eye to the brain in vivo. He found that over-expressing Bcl-2 in transgenic mice supported robust axon regeneration following optic nerve crush on postnatal day 3 (P3), but not in a later stage. Next, he explored the mechanisms causing the failure of optic nerve regeneration in mature Bcl-2tg mice. Dr. Cho discovered that the CNS environment expresses growth inhibitory molecules, at postnatal day five or later, that block axonal regeneration in vivo and in vitro.

Many studies have suggested that CNS glial cells, including astrocytes and oligodendrocytes/myelin, may contribute to the growth inhibitory effect in the CNS environment. By examining glial cell development in mouse brains, Dr. Cho demonstrated that the maturation of astrocytes, rather than myelin, correlates to the onset of growth inhibitory mechanism in the CNS at P5. Maturation of astrocytes seems to play a critical role in preventing CNS regeneration. This hypothesis was tested with the administration of the specific toxin (L-aminoadipate) against astrocytes in optic nerve of adult Bcl-2 transgenic mice. The result showed that L-aminoadipate could eliminate a majority of astrocytes and allow extensive axonal regeneration into the astrocyte-free area. Instead of using Bcl-2 transgenic mice, Bcl-2 can be induced in neurons of wild-type mice by feeding them with lithium-containing food. In combination with lithium-containing food and L-aminoadipate, this approach could induce the severed optic nerve to regenerate in wilt-type adult mice.

The role of astrocytes in suppressing optic nerve regeneration was further confirmed in a genetic mouse model, of which the scarforming activity of astrocytes is suppressed–mice deficient in astrocyte intermediate filament proteins, glial fibrillary acidic protein (GFAP) and vimentin. Dr. Cho generated the triple mutant mice by crossing Bcl-2tg mice to GFAP/Vimentin double knockout mice (G/VKO). In theory, neurons in these triple mutant mice maintain their intrinsic capacity to grow axons, while their astrocytes present less scar formation following injury. The data showed that robust optic nerve regeneration occurred in the triple mutant mice following optic nerve crush after postnatal day five and that regenerating axons reached their visual targets in the brain. This is the first report that a high proportion of RGC axons regenerate after injury over a long distance into the brain targets.

Taken together, the results suggest that the expression of Bcl-2 in neurons and the suppression of scar formation in CNS are crucial for robust CNS regeneration in adult mammals. This study provides insights that will be helpful in developing new strategies to treat CNS injury.

Projects

Research Interests

  • Neuron Degeneration and Regeneration

Neuroprotection of Photoreceptor Degeneration

Dr. Cho is exploring various strategies to protect against photoreceptor degeneration, such as electrical stimulation. He is also examining the role of endogenous retinal stem cells and stem cells-derived retinal progenitor cells to treat retinas with photoreceptor degeneration.

Mechanisms of Glaucoma

Glaucoma is a retinal degenerative disease that causes progressive loss of retinal ganglion cells and axons. Even if the intraocular level is well controlled, retinal degeneration still continues. Dr. Cho is investigating the role of various immune cells in disease progression and hopes to identify targets for glaucomatous degeneration.

Optic Nerve Regeneration

There are different players known to play a role in the regeneration of central nervous system including optic nerve. Dr. Cho's goal is to identify a key regulatory mechanism that promotes robust optic nerve regeneration. Recently, he has identified a novel protein that physically binds to a well known trophic factor, and thus, regulate the survival and axon regeneration of mature retinal ganglion cells. Now, he continues to investigate the downstream signaling pathway of this novel protein on axon regeneration.

Current Research Funding

2016-2018
National Eye Institute (NEI): Co-Principal Investigator (PI)
The big eye-dea: 3D single-cell resolution imaging of hte mouse eye using light sheet microscopy
2016-2021 NEI: Co-PI
The molecular basis under optic nerve growth in development and regeneration

Publications

H-index

13 (Google Scholar, as of May 2017)

Selected Publications

Dr. Cho has published more than 20 peer-reviewed articles and 3 chapters. Below is a list of selected publications. View his publications on PubMed or Google Scholar.

  1. Wu N, Wang Y, Yang L, Cho KS. Signaling Networks of Retinal Ganglion Cell Formation and the Potential Application of Stem Cell-Based Therapy in Retinal Degenerative Diseases. Hum Gene Ther. 2016 Aug;27(8):609-20.
  2. Cho KS, Guo C, Chew J. Yuan JC. Zhu R, He Z, Chen DF. Neuroscience and Diseases: Neural Regeneration, Ch12: "The Intrinsic Determinants of Axon Regeneration in the Central Nervous System." p197-208. So, Kowk-Fai; Xu, Xiao-Ming (Eds.) Science Publishing House, Shanghai Branch. 2015
  3. Fang Y,* Cho KS,* Tchedre K, Lee SW, Guo C, Kinouchi H, Fried S, Sun X, Chen DF. Ephrin-A3 suppresses Wnt signaling to control retinal stem cell potency. Stem Cells. 2013; 31(2):349-59.
  4. Yang Q,* Cho KS,* Chen H, Yu D, Wang WH, Luo G, Pang IH, Guo W, Chen DF. Microbead-induced ocular hypertensive mouse model for screening and testing of aqueous production suppressants for glaucoma. IOVS. 2012; 53(7):3733-41.
  5. Cho KS, Yang L, Ma HF, Lu B, Huang XZ, Pekny M & Chen DF. Re-establishing the regenerative potential of CNS axons in adult mice. J Cell Science. 2005; 118(Pt 5), 863-72.

* These authors contribute equally and considers as first author.