Sheldon S. Miller, Ph.D.
Section on Epithelial and Retinal Physiology and Disease
Over the last several decades we have been able to provide a comprehensive analysis of plasma membrane proteins and intracellular signaling pathways that mediate human retinal pigment epithelial (RPE) cell physiology and its interactions with retinal photoreceptors. This work includes the development of pre-clinical animal models of disease, including choroidal neovascularization (CNV) in age-related macular degeneration (AMD) and retinal re-attachment, which has provided the basis for several recent clinical trials. At the molecular level, we identified micro RNAs enriched in human RPE compared to adjacent retina and choroid. We showed how several of these micro RNAs help maintain tight junction integrity, RPE physiology, and epithelial phenotype. We have identified a signature set of genes that distinguish human RPE from other cells in the body. Using a similar approach, we have identified several hundred additional genes that distinguish human fetal and adult RPE tissue. In recent efforts, we provided a molecular and physiological characterization of RPE tissues derived from a number of extant induced pluripotent stem cell (iPS) lines. This work helps us understand the basis for variability in RPE cells derived from iPS cells of different genetic and epigenetic origins. We identified a signature set of molecular and physiological assays that operationally define authentic RPE tissue derived from genetically diverse cell types. This work provided a first step toward the development of a rational basis for a consistent, successful, and safe therapeutic intervention in retinal/RPE diseases using iPSC technology. Currently we are developing an autologous cell therapy using iPS cell – derived RPE for age-related macular degeneration (AMD). In parallel, we are using iPS cell-derived RPE to study the mechanisms of disease initiation in several monogenic neurodegenerative disease and AMD.
Dr. Miller received his B.S. in physics from Case Institute of Technology, his M.S. in elementary particle physics from Ohio State University, and Ph.D. in biophysics from the University of Michigan. His post- doctoral work was at the University of California, San Francisco, in the Department of Ophthalmology where he carried out with Roy Steinberg the first studies on retinal pigment epithelial transport. Dr. Miller was appointed as an assistant professor in the Vision Science Program and The School of Optometry at UC Berkeley, and full professor in 1984. In 1988, he was appointed professor in the Department of Molecular and Cell Biology at UC Berkeley. His honors include a NIH - Research Career Development Award and a NIH - MERIT Award. In 2002, he was recruited as Director of Intramural Research in the National Eye Institute. Dr. Miller’s research interests have focused on understanding the function and regulation of epithelia from breast, lung, and eye with particular interest in the pathophysiology associated with disease processes such as breast cystic disease, cystic fibrosis, and retinal degenerative diseases leading to abnormal fluid accumulation in retina and subretinal space.