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Biography
My research on the biology of RPE cells, and especially their pigmentation, has been ongoing since my graduate studies in the 1990s. As the principal investigator on this ‘multipartite’ application I bring my experience at successfully participating in and leading multidisciplinary groups toward a common goal. For example, I participated in the international Spheramine clinical trials (NCT00206687, BAY865280) in which cultured fetal human RPE were produced as tissue-type monolayers on small crosslinked gelatin beads, then surgically implanted in the brains of patients with Parkinson’s disease. The basis of this procedure is that all pigmented cells release L-DOPA, which is produced as a byproduct of melanin synthesis. During this research, where I tested many batches of RPE cultures for trophic activity and L-DOPA production, it became very clear that RPE pigmentation was the key factor in determining their trophic potential. I participated as a member of the team in this study from 2005-2009, my role was to culture RPE cells on beads and characterize them for numerous activities that would be either beneficial or detrimental when implanted into a patient’s brain. Upon closure of the stage two trial, I turned my attention to probing the linkage between pigmentation and RPE neurotrophic activity. This focus led to my identification of the L-DOPA receptor expressed by RPE, GPR143, and the downstream signaling activities of the receptor. We illustrated RPE exosome release as a primary event tied to GPR143 signaling, GPR143 signaling halts RPE exosome release. Exosomes drive angiogenesis and are likely to participate in the angiogenic disease process of neovascular AMD. We then asked whether AMD patients benefitted from L-DOPA supplementation. The question was simple, but required me to establish and lead a new team of collaborators. I met potential collaborators at ARVO, a made a lot of cold phone calls to develop a new team, most of whom I had never met. In the end, I brought together a team of 13 new collaborators to ask, ‘are patients prescribed L-DOPA protected from AMD?’. The answer was yes. This led me to establish a new team of local clinicians to prospectively test whether L-DOPA treatment benefits patients with AMD. Again, the answer was yes. However, developing and leading this team, on an unfunded study that directly confronts an AMD clinicians’ earnings, was not trivial, and demonstrates both my commitment and my leadership skills. We successfully completed and published this study, the first showing the GPR143 signaling may be beneficial for patients with AMD. Significant more needs to be done before it will be ready for broad use, but we did show the pathway. In the proposal here, we ask a new and novel question, ‘how does zinc absorption from the diet, transport to RPE, and accumulation in pigment granules controlled by GPR143 signaling, affect AMD? Zinc was identified beneficial to a subset of people in the AREDs trials, but the detailed mechanism remains unexplored.
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R01 EY026544-01
M2010074
Works (43)
PPR18661