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Noncanonical Autophagy and Toll-Like Receptor Signaling in SLE
There is increasing evidence that dysregulated toll-like receptor (TLR) signaling in response to endogenous nucleic acids contributes to SLE pathogenesis. We have recently identified a role for autophagy in regulation of TLR signaling in B cells and plasmacytoid DCs (pDCs) The overall aim of this project is to determine whether SLE risk variants in the autophagy component ATG5 affect TLR-induced autophagy and whether this regulatory pathway is disrupted in lupus. We propose studies to analyze TLR signaling responses in pDCs from healthy individuals with ATG5 SNPs and in SLE patients, making use of genotyped samples from SLE patients and healthy volunteers collected as part of the BRI Immune Repositories. These experiments will be combined with genetic studies to determine the genes involved in TLR-induced autophagy in pDCs. Work in year one of this project has been focused on establishing robust assays to measure these processes and initial analysis of patient samples. Experiments are underway to determine whether cytokine responses are altered in pDCs from healthy controls and SLE patients.
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