Rong Wen, M.D., Ph.D.
Photoreceptor Degeneration, Age-Related Macula Degeneration, Diabetic Retinopathy
Retinal Degeneration and Vascular Disorders
As a retinal cell biology lab, we focus on the changes in photoreceptor behaviors under different circumstances. Specifically, we are interested in the mechanism that regulates light-induced photoreceptor plasticity and the role of Müller cells in this regulatory mechanism. We are also trying to understand the mechanisms for photoreceptor degeneration, including hereditary retinal degeneration and age-related macular degeneration (AMD), and to search for potential treatments. In addition, we are developing experimental models to mimic human ocular vascular disorders including choroidal neovascularization (CNV) and diabetic retinopathy. The goal is to understand the biology of the retina and photoreceptors, the physiopathology of retinal diseases, and to translate the bench research to patient care.
The long-term objective is to understand the diseases and to improve clinical treatments. Research in this laboratory focuses on understanding how cells behave in the healthy retina and how the normal behaviors change in conditions that lead to diseases. The three diseases we focus on are inherited retinal degeneration, age-related macular degeneration, and diabetic retinopathy.
Light-induced photoreceptor plasticity was discovered more than 30 years ago when scientists noticed that photoreceptors change their light sensing capability with the environmental lighting. When animals were moved from relative strong environmental lighting to darkness, photoreceptors increase their photon catching capability, and they reduce the lighting sensing capability when they are moved from dim environmental lighting to stronger one. However, how photoreceptors in the entire retina coordinate their changes and the underlying mechanism is not understood. Our work leads us to believe that Müller cell, the major glial cells in the retina, play a central role in regulating light-induced photoreceptor plasticity.
Inherited retinal degenerations are a major cause of blindness with no effective treatments available. It is estimated that one in 3,500 to 4,000 people is affected by retinitis pigmentosa (RP), a heterogeneous group of inherited retinal degenerative disorders. During early stages, patients typically experience night blindness and decline in peripheral vision, due to loss of rod photoreceptors. Central vision is eventually affected as secondary cone degeneration progresses, leading to complete blindness. Mutations in more than 100 genes are implicated in RP.
Although there is no approved treatment available for retinal degeneration, several treatment strategies are under active study. One such strategy is to protect photoreceptors by neurotrophic factors, factors that influence the survival, function, and other behaviors of neurons and other cells in the nervous system. CNTF (ciliary neurotrophic factor) has been identified as a factor that promotes photoreceptor survival in a variety of animal models across several mammalian species. Several clinical trials have been successfully completed and more are expected. Our research to understand the basic mechanism of CNTF neuroprotection has provided and will continue to provide experimental data to support the potential clinical application.
In most inherited retinal degenerations, the genetic mutations affect primarily rod photoreceptors, not cone photoreceptors. However, after rod degeneration, cones degeneration follows, a phenomenon known as the secondary cone degeneration. In collaboration with Dr. Yiwen Li of Bascom Palmer Eye Institute, we have characterized the secondary cone degeneration in an experimental model. Our work demonstrated that neurotrophic factors, including CNTF, could actually reverse the cone degenerative process. We are currently creating a model to advance our understanding of cone degeneration.
Recently, a team work by investigators from Bascom Palmer Eye Institute, John P. Hussman Institute for Human Genomics, Dr. John T. MacDonald Department of Human Genetics, Department of Interactive Biology, Department of Biochemistry and Molecular Biology, and this lab, led to the discovery of a novel mutation in the DHDDS gene as a cause of retinal degeneration. Unlike the “typical” mutations that cause retinal degeneration, this mutation reduces the activity of DHDDS that affects all cells in the body and yet, the only manifestation is retinal degeneration. We believe the unique metabolic demand of photoreceptors makes them most vulnerable to the reduced DHDDS activity. We are developing several experimental models for this disease in order to facilitate our understanding of it and to test several treatment strategies, including gene therapy and neuroprotective therapy.
Age-related macular degeneration (AMD) is a leading cause of irreversible blindness in people over 65 of age in the western world. The exudative form of AMD (wet AMD) characterized by choroidal neovascularization (CNV), accounts for majority of the cases with severe loss of vision. We have developed an experimental model to mimic CNV in human by injecting Matrigel between photoreceptors and the RPE (retinal pigment epithelium). We have used this model to study the inhibition of CNV by experimental inhibitors and to study the inflammatory reaction in CNV.
Diabetic retinopathy remains a leading cause of severe vision loss and blindness in the developed world. Although in the early stage of the disease vision is not immediately impaired in patients, the proliferative stage of the disease could result in loss of vision due to leaky blood vessels in the retina that lead to edema and hemorrhage. Experimentally inducing diabetes in laboratory models failed to induce proliferative retinopathy, however. The lack of suitable models has hampered the progress of diabetic retinopathy research and the development of new effective treatments. We are working on several strategies to induce diabetic retinopathy in experimental models.