SUMMARY OF RESEARCH DURING 2013
(3MD's/PhD's, 15 MD’s; 9 PhD’s; 2 other; 44 publications; 2 book chapters distributed in 2 books)
Significant Scientific Accomplishments
We continue to expand our understanding of how interactions between retinal metabolism, environmental stress and genetic mutations lead to blindness through 3 major research areas.
Area 1: Cellular and Biochemical Studies of Induced-Stress on RPE Cells
- Research: Stress on RPE cells is presumed to lead to visual defects. The contribution of smoking, an AMD-risk factor, was studied to better understand the pathophysiology of AMD development. The effects of glycated end-products as seen in diabetes were studied for loss of the RPE cells’ ability to clear subretinal fluid.
- Results: Smoke activated the alternative pathway of the complement system in RPE cells and resulted in lipid accumulation. The latter could be prevented with a complement inhibitor. Intravitreal injections of glycated albumin resulted in reduced ability of the RPE to clear subretinal fluid; C-type natriuretic peptides restored normal RPE function.
- Significance: Chronic stresses, such as from smoking or glycated proteins, can lead to loss of function or viability of RPE cells.
Area 2: Retinoid Processing in Photoreceptors and RPE
- Research: Researchers determined the distribution of A2E (a byproduct of the visual cycle) and lipofuscin in the RPE of human donor eyes at different ages. Retinoid metabolism that can lead to A2E or cell toxicity was also studied in individual human photoreceptor cells.
- Results: Fluorescence microscopy and mass spectrometry showed A2E localization in the periphery of the human RPE, a result that inversely correlates with lipofuscin. Characterization of retinoid metabolism in single human photoreceptor cells has also been initiated.
- Significance: Limiting A2E is a current strategy for treating Stargardt, AMD, and other diseases. Our findings suggest the field will need to rethink the validity of this.
Area 3: Development of Patient-Specific Human Induced-Pluripotent Stem Cells (iPSCs)
- Research: Stem cells are being derived from AMD patients to generate patient-specific cells for the potential replenishment of degenerated retinal cells.
- Results: Patients are being recruited under IRB-approved studies. iPSCs have been generated from AMD patients. RPE cells are being derived and characterized from these iPSCs.
- Significance: The ability to generate RPE cells from the patient’s own cells has great potential for customized treatment that avoids tissue rejection upon cell transplantation.