Non-canonical NLRP3 Inflammasome activation in Geographic Atrophy

  • Kerur, Nagaraj (PI)
  • Ambati, Jayakrishna (CoI)

Grants and Contracts Details


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) degeneration. Currently there is no therapy available for 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 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., Nature 2011; Tarallo et al., Cell 2012). Various signaling pathways control the checkpoints regulating NLRP3 inflammasome activation at multiple steps. A comprehensive understanding of these molecular determinants of inflammasome activation is critical for developing rational NLRP3 inflammasome-targeting 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 develop functional insights into how NLRP3 inflammasome signaling is regulated in GA pathogenesis in the context of Dicer1/Alu dysregulation via the following aims: (1) Unveiling the mechanism of non-canonical NLRP3 inflammasome priming in Alu RNA induced GA pathogenesis; (2) Deciphering the role of caspase-4 (aka caspase-11 in mouse) in Alu RNA-induced NLRP3 activation and RPE degeneration; (3) Defining the mechanisms of caspase-4-mediated regulation of NLRP3 inflammasome in Alu RNA-induced RPE cell degeneration. These studies will illuminate the molecular foundation of GA, and unravel novel regulatory checkpoints of NLRP3 inflammasome activation.
Effective start/end date4/1/1412/31/15


Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.