Micro-RNA independent Dicer signaling in inflammation and atherosclerosis

Atherosclerosis is an aseptic inflammatory disease arising from focal endothelial dysfunction followed by the recruitment of circulating inflammatory cells. The mechanisms that govern these initial endothelial/leukocyte interactions are incompletely understood. Our group was the first to identify the importance of micro-RNA-independent Dicer activity in maintaining cellular homeostasis through enzymatic degradation of endogenous inflammatory RNAs. Dicer-mediated enzymatic clearance of Alu RNA transcripts (which are short, non-coding RNAs derived from genetically encoded Alu repeat elements) prevents activation of the NLRP3 inflammasome and cellular apoptosis. However, the consequences of a loss in Dicer activity, and the subsequent accumulation of these RNA transcripts on vascular inflammation and atherosclerosis are not known. The central aim of this proposal is to determine whether Dicer, through its constitutive degradation of inflammatory RNAs, prevents atherosclerosis by suppressing pro-inflammatory responses in vascular cells. Therefore, my overall hypothesis is that through its enzymatic degradation of non-canonical RNA substrates, Dicer plays an essential surveillance role to prevent vascular inflammation and atherosclerosis. This hypothesis will be tested by the following specific aims: 1) To determine Dicer and its RNA substrates are dysregulated in atherosclerosis; 2) To determine the regulatory role of non-canonical Dicer signaling in endothelial/leukocyte inflammation; 3) To determine whether endothelial Dicer activity prevents atherosclerosis. This proposal will integrate molecular, cellular, animal and human disease models to answer the overall hypothesis.