Zhang Y. Role in Myopia Development of Retinal Pigment Epithelium - A New Therapeutic Target ? Project Summary The Mentored Clinical Scientist Research Career Development Award (K08) candidate, Yan Zhang, earned her clinical degrees in Medicine and Ophthalmology, and she is currently pursuing her Ph.D. degree in the Vision Science Program at University of California, Berkeley, which will be completed in the Spring 2013. She has already one publication in a high profile journal from the latter research, with 2 more papers soon to be submitted, demonstrating both good productivity and research drive. As the next step towards a career as an independent clinician scientist in academia, Dr. Zhang is applying for a K08 career award to obtain advanced training - to further expand her scientific knowledge and biomedical technical skills through investigations into the roles of retinal pigment epithelium (RPE) and bone morphogenetic proteins (BMPs) in eye growth regulation and myopia development, with the RPE targeted in related exploratory studies of gene therapy for myopia treatment. Over the course of her studies to-date, Dr. Zhang has received broad training in many of the disciplines required for successfully executing her proposed project. She proposed to cover remaining deficiencies with additional coursework and hands-on training during the 5-year training period of the K award for which she is applying. Thus at the end of this 5-year career development award Dr. Zhang should be well prepared for a career as an independent researcher, successfully competing for research funds. The proposed study will be conducted primarily under the mentorship of Dr. Christine Wildsoet, who is a well- known leading scientist in the field of myopia and eye growth regulation. Myopia, or nearsightedness, is one of most common refractive errors in humans and significantly contributes to the global burden of eye disease. It is the product of eyes growing excessively long. The prevalence and the severity of myopia have risen worldwide during the past several decades, stimulating increased research into the underlying mechanisms, an essential step in developing effective anti-myopia therapies. Previous studies have suggested that early eye growth regulation is largely localized to eye itself. The RPE is known to be a component of the blood-retina barrier, with critical roles in maintaining normal retinal and choroidal functions. Recent research findings, mostly from the Wildsoet lab and much of it belongs to Dr. Zhang, suggest that it also plays an essential role in the regulation of eye growth. The proposal focuses on the role of RPE in myopia development and as a potential target for myopia therapy, with 3 specific aims: (1) to investigate the role of RPE-derived bone morphogenetic proteins (BMPs) in eye growth regulation; (2) to investigate the effects of dopamine (DA) on RPE-BMP expression and secretion; (3) to investigate over-expression of BMPs in RPE as a potential gene therapy for myopia. Complementary experiments include in vivo animal studies, using the chick as an myopia model, and in vitro cell culture studies, using human fetal (hf) RPE as a model, exploiting Dr. Zhang's experience with both models. In vivo structural and functional measurements will use advanced technologies, including high frequency A-scan ultrasonography, spectral domain optical coherence tomography (SD-OCT) and electroretinography (ERG). A variety of molecular and cell biology techniques will also be used including cloning, real-time PCR, Western blot, ELISA, and immunohistochemistry. Techniques most commonly encountered in ocular gene therapy research, including electroporation and subretinal injection, will also be employed. The proposed research will be conducted under the co-mentorship of Dr. Jeanette Hyer from UC San Francisco, who is an expert in developmental biology, with a focus on chick embryogenesis. Three senior scientists have also agreed to serve as consultants on her project: Professor Lawrence Rizzolo (Yale University) and Dr. Sheldon Miller (NEI/NIH), who are experts in RPE physiology and electrophysiology, and Professor Kunxin Luo (UC Berkeley), whose research focus is the TGF- family including BMPs and their roles in cell differentiation, tissue morphogenesis, and extracellular matrix production. UC Berkeley and UC San Francisco offer world-class research environments and support for the preparation and training of young scientists for independent research careers.