My laboratory studies age-related macular degeneration (AMD), the leading cause of vision loss among the elderly in the US and other western countries. This complex disease is characterized by death of the light-sensing photoreceptors cells in the macula region near the center of the retina. As a consequence, patients progressively lose their central vision. Clinical and animal studies indicate that oxidative stress is a root cause of AMD. In the simplest terms, oxidative stress occurs when cells accumulate reactive oxygen species (ROS). These ROS are derivatives of the oxygen we breathe, and they can damage the building blocks of cells (e.g. proteins, DNA, and lipids). They are the reason that anti-oxidants such as vitamins C and E protect our cells from harm. Unfortunately, the cells of the eye are exquisitely sensitive to damage by ROS, and are constantly subjected to ROS derived from excessive sunlight exposure and cigarette smoke, major risk factors for AMD.
It is believed that photoreceptors in the macula die as a secondary consequence of chronic oxidative stress in neighboring cells called retinal pigment epithelial (RPE) cells. One can think of RPE cells as the guardians or caretakers of photoreceptors. These cells form a single layer that makes direct physical contact with photoreceptors and they function to provide nutrients, such as vitamin A, to the photoreceptors.
Our research program focuses on two main areas. One focus is to understand how chronic oxidative stress debilitates the mitochondria in RPE cells. Mitochondria are the energy-producing machines in our cells and AMD patients suffer a loss of functional mitochondria from their RPE cells. But, exactly how this happens and its ramifications on the capacity of these cells to care for photoreceptors are unknown. Our other focus is to identify strategies that increase the capacity of RPE cells to block the damage caused by oxidative stress. Together, these efforts have the potential to advance the development of therapeutics to prevent and treat AMD.
Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss in people over 60 years of age. The pathogenesis of this disease is multifactorial and appears to involve a combination of environmental, metabolic, and genetic inputs. A mounting body of clinical and experimental evidence supports the idea that chronic oxidative stress in the retinal pigment epithelium (RPE) is a precipitating event in photoreceptor death and AMD onset. Yet, clinical studies have shown that high dose, oral anti-oxidant therapy only moderately slows the progression of advanced macular degeneration. The disconnect between these observations and outcomes highlights a growing consensus that free radicals can have both essential and deleterious consequences for cellular health. We are clearly only beginning to understand the fundamental roles of free radicals and oxidative stress in the context of AMD onset and progression. This knowledge gap is arguably a primary barrier to developing targeted interventions.
The research in our laboratory focuses on understanding (1) how RPE cells are affected by chronic oxidative stress and (2) the endogenous mechanisms these cells use to mitigate oxidative damage. We are currently pursuing studies to elucidate the consequences of oxidative stress on the integrity and function of the mitochondrial network in RPE cells. In complementary studies, we are continuing our efforts to determine how the ubiquitin proteolytic system protects against the accumulation of oxidatively-damaged biomolecules and contributes to regulating the anti-oxidant capacity of RPE cells. Specifically, we are studying a ubiquitin conjugating enzyme, called UbcM2, and the mechanisms by which this enzyme regulates the stability and function of Nrf2, the master anti-oxidant transcription factor in the RPE.
We are using a variety of experimental approaches including: (i) genetic, chemical, and environmental mouse models of oxidative stress-induced retinopathy, (ii) cell culture and reconstitution assays to dissect the molecular mechanism(s) by which UbcM2 regulates Nrf2, and (iii) live-cell video microscopy to track changes in mitochondrial dynamics in response to oxidative stress. Our overarching goal is to apply the knowledge gained from this work to the development of vision-sparing therapeutics.
B.S., Rutgers University College of Pharmacy, Piscataway, NJ, 1992
Ph.D., Johns Hopkins University, School of Medicine, Baltimore, MD, 1998
Postdoc, University of Virginia, Center for Cell Signaling, Charlottesville, VA, 1998
Honors & Awards
2009 Young Investigator Travel Award, American Diabetes Association 69th Annual Meeting, New Orleans, LA
2008 Travel Fellowship, XVIIIth International Congress of Eye Research, Beijing, China
2008 Travel Fellowship, XIIIth International Symposium on Retinal Degenerations, Emeishan China
2004 Oklahoma Center for the Advancement of Science and Technology New Scientist Award
2002-2003 American Cancer Society Postdoctoral Fellowship
2000-2001 Postdoctoral Individual National Research Service Award – National Institutes of Health
1992 Rutgers University, College of Pharmacy Analytical Chemistry Award
1992 Rutgers University, College of Pharmacy Student Research Award
American Association for the Advancement of Science
American Diabetes Association
American Society of Cell Biology
Association for Research in Vision and Ophthamology
International Congress of Eye Research
Joined OMRF Scientific Staff in 2011
Borcherding DC, Siefert ME, Lin S, Brewington J, Sadek H, Clancy JP, Plafker SM, Ziady AG.. Clinically-approved CFTR modulators rescue Nrf2 dysfunction in cystic fibrosis airway epithelia. J Clin Invest 130, 2019 May, PMID: 31145101, PMCID: PMC6668689
Chen C1, Zhong Y, Wang JJ, Yu Q, Plafker K, Plafker S, Zhang SX. Regulation of Nrf2 by X Box-Binding Protein 1 in Retinal Pigment Epithelium. Front Genet 9:658, 2018 December, PMID: 30619478, PMCID: PMC6306429
O'Mealey GB, Plafker KS, Berry WL, Janknecht R, Chan JY, Plafker SM. A PGAM5-KEAP1-Nrf2 complex is required for stress-induced mitochondrial retrograde trafficking. J Cell Sci. 2017 Oct 15; 130(20):3467-3480. Epub 2017 Aug 24. PMID: 28839075 PMCID: PMC5665445
Chen M, Nowak DG, Narula N, Robinson B, Watrud K, Ambrico A, Herzka TM, Zeeman ME, Minderer M, Zheng W, Ebbesen SH, Plafker KS, Stahlhut C, Wang VM, Wills L, Nasar A, Castillo-Martin M, Cordon-Cardo C, Wilkinson JE, Powers S, Sordella R, Altorki NK, Mittal V, Stiles BM, Plafker SM, Trotman LC. The nuclear transport receptor Importin-11 is a tumor suppressor that maintains PTEN protein. J Cell Biol. 2017 Mar 6;216(3):641-656. Epub 2017 Feb 13. PMID: 28193700 PMCID: PMC5350510
Larabee CM, Desai S, Agnieshka A, Georgescu C, Wren JD, Axtell RC, Plafker SM. Loss of Nrf2 exacerbates the visual deficits and optic neuritis elicited by experimental autoimmune encephalomyelitis. Mol Vis. 2016 Dec 30;22:1503-13. PMID: 28050123 PMCID: PMC5204460
Larabee CM, Hu Y, Desai S, Georgescu C, Wren JD, Axtell RC, Plafker SM. Myelin-specific Th17 cells induce severe relapsing optic neuritis with irreversible loss of retinal ganglion cells in C57BL/6 mice. Mol Vis. 2016 Apr 11; 22: 332-41. eCollection 2016. PMID: 27122964 PMCID: PMC4830397
Plafker KS, Plafker SM. The ubiquitin conjugating enzyme, UBE2E3 and its import receptor, Importin-11 regulate the localization and activity of the anti-oxidant transcription factor Nrf2. Mol Biol Cell. 2015 Jan 15;26(2):327-38. Epub 2014 Nov 5. (Cover photo and article highlighted in ASCB newsletter) PMID: 25378586 PMCID: PMC4294679
Aging & Metabolism Research Program, MS 21
Oklahoma Medical Research Foundation
825 N.E. 13th Street
Oklahoma City, OK 73104
Phone: (405) 271-1735, (405) 271-1745
Fax: (405) 271-1437