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 made the surprising observation that there is an abundance of Alu repetitive RNA in the RPE of human eyes with GA that accumulates in response to a dramatic deficiency in the RNase DICER1 and induces RPE degeneration (Kaneko et al. Nature 2011). Our findings, which introduce a novel cell survival function for DICER1 independent of its canonical miRNA biogenesis function and the concept that Alu RNA can directly promote human pathology, provide new mechanistic insights into GA pathogenesis. However, we still lack an integrated understanding of how DICER1 is dysregulated in GA and precisely how Alu RNA induces 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 DICER1/Alu RNA dysregulation contributes to GA pathogenesis and develop a novel therapeutic strategy via the following Aims: (1) Generate a spatiotemporal map of DICER1 and Alu RNA in relation to the locus of pathology in GA and early AMD eyes;(2) Decipher the mechanisms by which Alu RNA triggers a new inflammatory cell death pathway we have identified;(3) Define the molecular regulation of DICER1 in the RPE in the context of GA and the function of a novel DICER1 splice variant;(4) Create a new animal model of GA having human-like features of the disease and validate an antisense therapeutic strategy targeting Alu RNA. 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 perfectly aligned with the 5-year goals of the NEI's Retinal Diseases Program strategic plan.
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 in the eyes of patients with GA. The goal of this project is to understand how this newly discovered pathway causes GA, and to test drugs that will be suitable for entry into clinical trials.
|Kim, Younghee; Tarallo, Valeria; Kerur, Nagaraj et al. (2014) DICER1/Alu RNA dysmetabolism induces Caspase-8-mediated cell death in age-related macular degeneration. Proc Natl Acad Sci U S A 111:16082-7|
|Hirano, Yoshio; Yasuma, Tetsuhiro; Mizutani, Takeshi et al. (2014) IL-18 is not therapeutic for neovascular age-related macular degeneration. Nat Med 20:1372-5|
|Fowler, Benjamin J; Gelfand, Bradley D; Kim, Younghee et al. (2014) Nucleoside reverse transcriptase inhibitors possess intrinsic anti-inflammatory activity. Science 346:1000-3|
|Chavala, Sai H; Kim, Younghee; Tudisco, Laura et al. (2013) Retinal angiogenesis suppression through small molecule activation of p53. J Clin Invest 123:4170-81|
|Ambati, Jayakrishna; Atkinson, John P; Gelfand, Bradley D (2013) Immunology of age-related macular degeneration. Nat Rev Immunol 13:438-51|
|Kerur, Nagaraj; Hirano, Yoshio; Tarallo, Valeria et al. (2013) TLR-independent and P2X7-dependent signaling mediate Alu RNA-induced NLRP3 inflammasome activation in geographic atrophy. Invest Ophthalmol Vis Sci 54:7395-401|
|Uehara, Hironori; Cho, YangKyung; Simonis, Jackie et al. (2013) Dual suppression of hemangiogenesis and lymphangiogenesis by splice-shifting morpholinos targeting vascular endothelial growth factor receptor 2 (KDR). FASEB J 27:76-85|
|Tarallo, Valeria; Hirano, Yoshio; Gelfand, Bradley D et al. (2012) DICER1 loss and Alu RNA induce age-related macular degeneration via the NLRP3 inflammasome and MyD88. Cell 149:847-59|