Geographic atrophy (GA) is an untreatable advanced form of age-related macular degeneration (AMD) that is characterized by degeneration of the retinal pigmented epithelium (RPE). Neither the mechanisms that promote this RPE degeneration nor the basis for the centrifugal expansion of GA that can ultimately lead to blindness have been resolved. This enigmatic nature of GA pathogenesis has precluded the development of any FDA-approved therapy for the one million Americans diagnosed with GA and the millions more at risk of developing GA. In new and exciting studies, we discovered an unconventional immune activation of the NLRP3 inflammasome complex in the RPE of human eyes with GA (Tarallo et al. Cell 2012) that occurs in response to a specific accumulation of toxic non-coding Alu RNAs during deficiency in the RNase DICER1 and induces RPE degeneration (Kaneko et al. Nature 2011). This surprising finding of pathologic inflammasome activation in a non-immune cell is a critical step in understanding GA pathogenesis and elucidating the essential effector pathways that determine retinal vitality. Our findings, which introduce a novel definition of auto-immunity: The RPE activation of the NLRP3 inflammasome in response to self-derived Alu RNAs represents the first description of inflammasome activation to endogenous, all the while causing pathology in a classically immune privileged ocular milieu. Crucially, blockade at multiple molecular steps along NLRP3 inflammasome activation blocked RPE cell death, thus providing an important mechanism-based strategy to alleviating the worldwide burden of GA. However, we still lack an integrated understanding of whether other AMD-related stressors also cause inflammasome activation in GA, and if so, precisely how these mechanisms converge upon common effector pathways that induce RPE degeneration. A rigorous definition of these mechanisms is crucial to enhancing our understanding of the molecular drivers of GA and to developing rational treatments. We will provide novel functional insights into how dysregulated NLRP3 inflammasome activation contributes to GA pathogenesis and develop a novel therapeutic strategy via the following Aims: (1) Generate a spatiotemporal map of known AMD-related stressors and markers of NLRP3 inflammasome activation in relation to the locus of pathology in GA and early AMD eyes;(2) Decipher the molecular mechanisms underlying inflammasome activation by known GA-associated stresses;(3) Determine whether blockade of inflammasome machinery and its effector pathways in acute and chronic animal models of AMD inhibit RPE degeneration. These studies will illuminate novel aspects of the molecular and biochemical bases of GA, and help validate a molecular targeting strategy that could be translated into clinical trials. As such, this proposal is aligned with the -year goals of the NEI's Retinal Diseases Program strategic plan.

Public Health Relevance

There is no FDA-approved treatment for the one million Americans with geographic atrophy (GA) or for the millions more who are at risk of developing GA. We recently discovered an enzymatic deficiency that leads to accumulation of toxic RNA molecules and immune activation in the eyes of patients with GA. By understanding how these newly discovered pathways cause GA and testing therapies that will be suitable for advancing to clinical trials, this proposal is aligned with the National Vision Research Agenda's Needs, Gaps, and Opportunities for the NEI's Retinal Diseases Program strategic plan, and embraces the NIH Director's recent challenge to advance translational science using creative approaches.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
1R01EY024068-01A1
Application #
8757790
Study Section
Special Emphasis Panel (DPVS)
Program Officer
Mckie, George Ann
Project Start
2014-09-01
Project End
2018-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
1
Fiscal Year
2014
Total Cost
$657,112
Indirect Cost
$219,281
Name
University of Kentucky
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
Fowler, Benjamin J; Gelfand, Bradley D; Kim, Younghee et al. (2014) Nucleoside reverse transcriptase inhibitors possess intrinsic anti-inflammatory activity. Science 346:1000-3