May, 2011

Research Achievements

 Dr. Chen Zhao obtained his M.D. degree from Beijing University School of Medicine in 1997. After 5 years residency training in the Department of Ophthalmology in TongRen Hospital, Dr. Zhao launched his Ph.D. study in Tianjin Medical University majored in the Human genetics. During the period of Ph.D. study, he went to Karolinska Institute in Stockholm, where he spent 2 years as a visiting student under the guidance of Prof. Catharina Larsson, who is a member of the review board of Nobel Medicine Prize. Dr. Zhao has successfully discovered the genetic mechanism in a large number of families with various Hereditary Retinal Degenerations (HRDs). His brilliant works yield him a number of publications in the leading scientific journals (see appendix).

Bearing a great interest of molecular research of retinal degenerations, Dr. Zhao selected to continue his research in Stanford University in 2007, right after Ph.D study. In addition to continue the genetic study of retinitis pigmentosa (RP), he began to investigate the pathogenic mechanism of complex retinal degeneration (e.g. age-related macular degeneration, AMD) by using genetic mice tools. He has been leading investigators for two projects including the “Genetic Studies of TIMP3 in Exudative Macular Disease” and “Study of Retinal Degeneration in Mice Due to Loss of Retinal Pigment Epithelium (RPE) Mitochondrial Energy Production”.

Up to date, Dr. Zhao’s major scientific achievements include 1) The identification of SNRNP200 gene (p. hBrr2) as a novel adRP-causing gene, and in particular, the discovery of molecular basis for adRP caused by pre-messenger RNA splicing defect. A number of splicing factors were known to cause adRP with very high prevalence but the knowledge regarding the mechanism was extremely poor before Dr. Zhao’s study. Thus, this study, for the first time, provide a fundamental pathogenesis mechanism of splicing factors-related adRP that is derived from a defect in hBrr2-dependent RNA unwinding and a consequent defect in spliceosome activation. This work was published in the Journal of American Human Genetics (Am. J. Hum. Genet. 85:617-627, 2009). 2) Reveal an in vivo response of retinal pigment epithelium (RPE) to diverse stressors that prolongs RPE cell survival at the expense of epithelial attributes and photoreceptor function. This is a novel pathogenesis mechanism of AMD to challenge the prevailing central tenet that emphasizes the role of RPE death. More importantly, these findings point out the inhibition of the mTOR pathway as a promising therapeutic strategy for AMD and other retinal degenerative diseases involving RPE stress. This outstanding work was published in the Journal of Clinical Investigation (12/7/2010, Epub ahead on line).

Dr. Zhao has also made important contributions to strengthen US-China relationship in regarding to the collaboration on ophthalmology education and vision research. He has been involved in launching the education program for Chinese ophthalmologists, which is operated by the Chinese Ophthalmology Society (COS) and American Association for Pediatric Ophthalmology and Strabismus (AAPOS). This program is going very well and has provided great beneficial for local China Ophthalmologists. In addition, Dr. Zhao has also facilitated the research collaborations for Tianjin Eye Hospital and Tianjin Medical University with several partners including Prof. Jonathan Staley’s lab in University of Chicago, Prof. Douglas Vollrath’s lab in Stanford University, Prof. Qing Wang’s lab in the Cleveland Heart Center, Prof. Ji-jing Pang’s lab in University of Florida and Prof. Li-jin Dong’s lab in National Eye Institute. All of the collaborations have been extensively helpful, which can be demonstrated by a number of publications with high impact. The collaborations are still ongoing with Dr. Zhao being the key person. The collaborations will certainly be critical to improve the quality of China local research works in future. 

May 2010

The New idea from Dr. Dong Chen, MD, PhD, Harvard Medical School, Harvard Schepens Eye Research Institute, USA.

Blame epigenetic, not your genes

A commonly accepted definition of epigenetics would be the study of heritable changes that are not caused by changes in the nucleotide sequence of the DNA. Epigenetics studies the additional layers of information on top of the bare genomic sequence that permit the cells to respond to certain environmental cues and confer phenotypic plasticity. It has become clear that epigenetic changes play a key role in normal development as well as in disease processes.

With this being said, I will cite the words of Thomas Jenuwein (Vienna, Austria): "The difference between genetics and epigenetics can probably be compared to the difference between writing and reading a book. Once a book is written, the text (the genes or DNA: stored information) will be the same in all the copies distributed to the interested audience. However, each individual reader of a given book may interpret the story slightly differently, with varying emotions and projections as they continue to unfold the chapters."

Thus, epigenetic modification of gene expression has allowed us the opportunity to take in charge, at least in part, of our genome that we inherit from parents.

From November 2009

Kang Zhang, MD, PhD, obtained his B.S. in Sichuan University in China in 1985.  He was the first Mainland Chinese student to earn both M.D. and PhD degrees from Harvard University and MIT since 1949.  He was the first Mainland Chinese to completed residency training in ophthalmology at Wilmer Eye Institute at Johns Hopkins University since 1949.  He completed his retina fellowship at University of Utah.  He was a faculty member at Johns Hopkins University, Cleveland Clinic Foundation, and University of Utah.  He is currently the Director of The Institute for Genomic Medicine, and Professor of Ophthalmology and Human Genetics at University of California San Diego.  

His honors include Burroughs Wellcome Fund Clinical Scientist Award in Translational Research; Chang Jiang Scholar Award, Lew Wasserman Merit Award from Research to Prevent Blindness; Charles Schepens Award for Excellence in Retina Research; and Johns Hopkins Medical Institutions Clinician Scientist Award.   He is a member of Macula Society, American Society of Clinical Investigation, and ASRS.  His research focuses on novel disease gene targets and therapies in macular degeneration, diabetic retinopathy, glaucoma and inherited retinal degenerations.  He has numerous grants from NIH, and other foundations.  He is a world leader in novel eye disease gene discovery and therapeutics development.  Dr. Zhang has published or co-authored more than 70 peer reviewed manuscripts in top journals including Science, New England Journal of Medicine, Nature, Nature Genetics, Nature Medicine, Cell, Genes and Development, PNAS, JCI -- covering topics in genetics, molecular biology, and clinical trials in ophthalmology.   His discovery of the HTRA1 gene as a major genetic risk factor for macular degeneration was named among Breakthroughs of the Year by the journal Science in 2006. 

Contribution from OCAVER Board member M H. Viet Tran, MD

Molecular diagnosis and management of inherited retinal diseases.

Some of interested topic in the study of inherited retinal disease include:  Exploring the effects of specific genetic mutations on retinal function in man using detailed psychophysics, retinal imaging and electrophysiology. Dr.Tran Current interests are in Leber�s Congenital Amaurosis and other forms of severe early onset retinal dystrophies, cone and cone rod dystrophies and inherited macular dystrophies.

 Developing new translational treatments for patient with retinal disease.

 Susceptibility genetic factors in age-related macular degeneration.

Contribution from OCAVER Board member Hong Liang, MD, PhD

One of my research topic concerns the toxicity of preserved eye drops, which receives little attention in ophthalmology field. Many research works showed that toxic preserved eye drops could induce ocular discomfort, tear film instability, conjunctival inflammation and apoptosis, corneal surface impairment, and potential risk for failure of further glaucoma surgery. The most frequently used preservative, benzalkonium chloride, has widely demonstrated its toxic effects in laboratory, experimental, and clinical studies. It damaged directly the cornea, the conjunctiva, the limbus, the lens and possibly the retina by releasing the pro-inflammatory cytokines or chemokines. These toxic effects are especially found in glaucoma, dry eye and allergic patients treated by these eye drops for a long time.

Contribution from OCAVER Board member David Huang, MD, PhD

Dr. David Huang is the Charles C. Manger, III, MD Chair in Corneal Laser Surgery and associate professor of ophthalmology and biomedical engineering at the University of Southern California (USC).  He is also the Medical Director of the Doheny Laser Vision Center ( www.dohenylaser.com ) at Doheny Eye Institute ( www.doheny.org ).  Dr. Huang earned the MD degree from Harvard University and a PhD in Medical Engineering and Medical Physics from Massachusetts Institute of Technology.   He received ophthalmology residency training at USC and fellowship training in cornea, external disease and refractive surgery at Emory University School of Medicine.  Prior to joining the USC faculty, Dr. Huang was on the staff of the Cole Eye Institute of the Cleveland Clinic. 

Dr. Huang is known for his innovations in applying laser and optical technology to eye diseases.  He is a co-inventor of optical coherence tomography (OCT), an imaging technology that has been applied to the measurement of eye structures with unprecedented precision.  His seminal article on optical coherence tomography, published in Science in 1991, has been cited more than 3300 times.  He has 8 issued patents and 6 pending patents in the areas of OCT, tissue engineering and corneal laser surgery.  He has been the principal investigator of 4 National Institutes of Health research grants.   He serves on the governing board, editorial board, program committee or advisory committee of 6 professional organizations.  He has published more than 80 peer-reviewed articles and edited 3 books.  Dr. Huang has received an Achievement Award from the American Academy of Ophthalmology and was selected as one of the Best Doctors in America ( www.bestdoctors.com ) and is listed on www.trustedlasiksurgeons.com, a directory service that screens LASIK surgeons based on research experience and premier patient care.  Dr. Huang leads the Center for Ophthalmic Optics and Lasers ( www.COOLLab.net ) at USC.

Contribution from OCAVER Board member Dr. Jijin Pang MD, PhD

Dr. Jijing Pang currently is a Research Associate Professor at Ophthalmology, University of Florida.

            Dr. Pang received his MD in 1988 from China Medical University. He became an attending doctor in Ophthalmology, 2^nd Affiliated Hospital of CMU in 1993 before he was sent to Japan for further training in research. Dr. Pang got his PhD in 1999 from Tokyo Medical and Dental University because of his finding on blue light damage to RPE cells. During his PhD course, Dr. Pang found a new type of Retinitis Pigmentosa due to vitamin E deficiency caused by an alpha-tocopherol transferase mutation. Oral administration of vitamin E stopped the progression of visual deterioration for the next 10 years. This experience prompted him to a postdoctoral position in Dr. Blanks’ lab at Oakland University in 1999. He tested adenoviral and lentiviral vectors via subretinal injections to rescue the photoreceptor degeneration seen in rd1 mice. Although the technical difficulties make the subretinal injection-related damage obvious in the mouse, especially in young pups, it is this gene replacement technique that captured his interest and remains the focus of his research program until he becomes a mouse expert.

            Dr. Pang moved to UF in 2002 with a well established mouse retinal surgery system. With rd12 mice, a model of LCA with Rpe65 mutation, he showed that AAV-mediated RPE65 expression lead to biochemical, structural, physioelectrical and behavioral rescues. Recently, Dr. Pang provides the proof that delayed treatment at P90 can rescue the function and morphology of the remaining M-cones, which has important implications for the current ongoing LCA2 clinical trials.

After this concept-proving program, Dr. Pang have expanded his retinal rescue program to many other mouse models of human retinal disease, for example, 1) the Cpfl5 mouse, a model of human achromatopsia with cnga3 mutations, 2) the rd10 mouse, a model of human retinitis pigmentosa with PDEmutations. Dr. Pang also collaborated with other researchers to rescue many other mouse models of human retinal degenerations, such as Cpfl3, rd6, rd17, GC-1-/-, LART-/- and Ccl2/Cx3cr1 deficient mice and RCS rat. Currently, nanoparticles systems are also being tested to widen the application of AAV vectors in retinal gene therapy, which has led to NIH R21 grant funding. Dr. Pang’s recent work on recue of mouse model of Achromatopsia leads to a grant funding as Co-PI from Florida State.

Dr. Pang has published 28 refereed journal articles and made more than 30 presentations at national meetings in the past 5 years. He also gave more than 40 invited seminar talks both nationally and internationally since 2003.

Dr. Pang has been a 2005-2006 Burns Visiting Professorship at University of Missouri-Columbia and 2009-2010 Visiting Professor in Wenzhou Medical College. He received H. Talmage Dobbs Ophthalmic Research Award from Emory Eye Center in 2003.