Non-canonical NLRP3 Inflammasome activation in Geographic Atrophy

  • Kerur, Nagaraj (PI)

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Geographic atrophy (GA) is an advanced form of Age-related macular degeneration (AMD) characterized by central loss of vision due to retinal pigmented epithelium (RPE) degenration. Currently there is no therapy available for patients with geographic atrophy, because of its elusive etiology. We recently provided novel mechanistic insights into the molecular underpinnings of GA and new opportunities for development of therapeutics. We discovered that DICER1 deficit causes a an unphysiological accumulation of Alu RNA transcripts in the RPE of human GA eyes and that Alu RNA activates the NLRP3 inflammasome, which in turn leads to MyD88-dependent RPE cell death (Kaneko et al., 2011; Tarallo et al., 2012). These studies have provided much needed mechanistic insights into understanding the GA pathogenesis, and have revealed the NLRP3 inflammasome as a novel therapeutic target for GA. Various of signaling pathways control the checkpoints regulating NLRP3 inflammasome activation at multiple steps. A comprehensive understanding these molecular determinants of inflammasome activation is critical for developing NLRP3 inflammasome-targeting rational therapeutic strategies for GA. In exciting, new studies we have discovered that caspase-4 (aka Caspase-11) is required for Alu RNA-induced NLRP3 inflammasome activation, suggesting an involvement of the non-canonical inflammasome in GA pathogenesis. Here we propose to gain functional insights into how caspase-4 regulates the NLRP3 inflammasome in GA pathogenesis in the context of Dicer1/Alu dysregulation via following aims: (1) Define the role of caspase-4 in Alu RNA-induced NLRP3 activation and RPE degeneration (2) Decipher molecular pathways regulating caspase-4-mediated NLRP3 inflammasome activation. These studies will illuminate the molecular foundation of GA, and unravel novel regulatory checkpoints of NLRP3 inflammasome activation.
Effective start/end date7/1/136/30/14


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