Modulating Lysosomal Function in Retinal Pigment Epithelial as a Novel Therapeutic Approach for the Treatment of AMD
Age-related macular degeneration (AMD) is the leading cause of blindness among the elderly and currently there is no known treatment for early AMD. Therefore, we want to focus our studies on this early phase of AMD in order to develop prevention and treatment before this disease advances and causes dramatic vision loss. Our proposed studies are aimed at developing novel small molecules that could be tested as a therapy for early AMD. Such studies have great clinical significance since they can provide a novel therapeutic approach for the management of early AMD.
Age-related macular degeneration (AMD) is the leading cause of blindness in elderly; with the population aging, the negative health impacts and costs of the disease will increase dramatically over the next decade. While effective treatment has been developed for advanced wet AMD and intermediate, dry AMD, currently there is no treatment or prevention for early AMD. Due to the large number of patients with early AMD, a new treatment that targets early disease at a stage before vision is lost would have the greatest benefit.
We have shown a novel function for the bA3/A1-crystallin molecule, which to the best of our knowledge is the only protein identified to date that is an upstream regulator of a major pathway linking amino acid availability to cell growth and autophagy, the V-ATPase/mTORC1 signaling axis. This signaling axis affects the retinal pigment epithelium (RPE), a layer of cells providing support to retinal neurons. bA3/A1-crystallin regulates this signaling axis by binding to V-ATPase, which is an evolutionarily ancient enzyme with remarkably diverse functions, including to acidify a wide array of intracellular organelles to assist in autophagy.
The V-ATPase/mTORC1 pathway is becoming a target for therapeutic interventions in age-related diseases, making bA3/A1-crystallin a potential therapeutic agent in AMD. While rapamycin or rapalogs have shown potential therapeutic efficacy for age-related pathologies in animal models, significant side effects limit their use in humans, mainly because they inhibit mTORC1 directly. Since bA3/A1-crystallin is an upstream regulator of mTORC1 and does not interact directly with mTORC1, it will offer new and safer modes of treatment for AMD.
Understanding the topology of this binding will allow the rational design of agents that can affect the binding, thereby modulating signaling through the mTORC1 pathway and potentially providing a novel therapeutic approach for the management of AMD.
About the Researcher
Debasish Sinha received his PhD degree in immunology and did a postdoctoral fellowship in molecular biology and genetics at the National Eye Institute. He is an associate professor in the Department of Ophthalmology, The Johns Hopkins University School of Medicine, with a joint appointment in the Department of Environmental Health Sciences, Bloomberg School of Public Health. He is also a faculty member for the Graduate Program in Pathobiology and Visual Neuroscience Training Program, Johns Hopkins University School of Medicine and a visiting faculty member in the Guest Professor Program of Tongji University, Shanghai, P.R. China. His laboratory uses rat spontaneous mutants and genetically engineered mice as genetic tools to explore the functions of glial cells during normal neuronal and vascular development and to probe how abnormalities in glial cells lead to central nervous system diseases. In addition, his laboratory also is interested in understanding the processes of autophagy and phagocytosis in retinal pigmented epithelial cells and regulation of the immune system in AMD. He is the chair of the Wilmer Science Seminar Series Committee, member of the Wilmer Research Meeting committee and director of the postdoctoral fellowship program at the Wilmer Eye Institute. He is currently the chair of the Professional Development and Educational Committee (PDEC) of the Association of Research in Vision and Ophthalmology (ARVO). Dr. Sinha’s research is funded by the BrightFocus Foundation, Bayer Healthcare, F. Hoffmann-La Roche, National Institutes of Health, Research to Prevent Blindness, and other private foundations. He received the Sybil B. Harrington Special Scholar award for Macular Degeneration from Research to Prevent Blindness and the Carolyn K. McGillvray Award for Macular Degeneration Research from BrightFocus Foundation. He has been an invited Member of the Arnold and Mabel Beckman Conference on Atrophic Macular Degeneration since 2012.
First published on: July 19, 2016
Last modified on: July 23, 2018