Sle1 on murine chromosome 1 and SleS on murine chromosome 7 represent 2 of the strongest loci for lupus in the NZM2410 mouse model. Whereas normal (B6)mice engineered to have Sle1 alone exhibit mild lupus, normal mice engineered to bear both loci develop severe lupus. Hence, B6, B6.Sle1z and B6.Sle1z.Sle3z congenic strains capture 3 distinct stages of disease development in lupus, reminiscent of the stages seen in human lupus development. More recently, we have documented that B-cells in these mice exhibit a progressive activation of multiple signaling pathways, including the AKT/mTOR axis, various MARK pathways, NFkB, STATS and STATS, and various Bcl-2 family members, with the levels of activation correlating well with disease severity. We have also learned that the candidate gene for the strongestsub- locus within Slelz, SLAM/Ly108, functions in a B-cell intrinsic fashion to breach early B-cell tolerance. Though the culprit genes for SleSz remain unknown, it is apparent that SleSz impacts the function of DCs and B-cells intrinsically. Based on these observations, we propose 3 Aims.
Aim 1. To ascertain if the signaling pathways upregulated in Slelz B-cells are the direct consequence of chronic stimulation by autoantigens and/or polymorphic differences between the normal and lupus- associated alleles/isoforms of Ly108. We will ascertain how chronic BCR stimulation, as well as the lupus- associated Ly108.1 and the """"""""normal"""""""" Ly108.2 isoforms of Sle1b/SLAM, might contribute to the signaling fingerprints observed in Slelz B-cells.
Aim 2. To distinguish between the B-cell intrinsic versus DC-dependent molecular mechanisms through which SleSz might contribute to B-cell activation in lupus. In addition to determining how SleSz affects B-cell signaling intrinsically, we will also elucidate the cellular and molecular mechanisms that may explain why lupus DCs may be better at """"""""helping"""""""" B-cells makeautoantibodies.
Aim 3. To ascertain the degree to which B-cell intrinsic activation of the AKT axis, or STATS (or other axes, where indicated) is necessary for the lupus phenotypes seen in B6.Slelz.SleSz mice. By ablating or hyper- expressing these molecules in a B-cell intrinsic fashion, we will ascertain how the activation of these 2 pathways in B-cells might contribute to lupus in B6.Slelz.SleSz congenic mice.
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