Targeting mTORC2 for lupus treatment

Project: Research project

Project Details

Description

Prior literatures have demonstrated that mTOR signaling, composed of mTORC1 and mTORC2 pathways, is elevated in lupus patients and mouse models of lupus. One of the key pathogenic cellular alterations associated with lupus severity is the increased differentiation of follicular helper T cells (Tfh), which drives high affinity antibody production by B cells. Our previous studies have demonstrated that both mTORC1 and mTORC2 critically contribute to Tfh differentiation. Furthermore, studies from our group and others have shown that mTORC1 is essential for naive T cell quiescence exit and differentiation of all effector T cell lineages, but mTORC2 preferentially promotes Tfh differentiation with minor contribution to other effector T cell lineages. Finally, elevated mTORC2 leads to regulatory T cell (Treg) instability, which eventually causes lupus-like autoimmunity in mouse models. Thus, we hypothesize that targeting mTORC2 can ameliorate lupus specifically through inhibition of Tfh and promotion of Tregs, without immune suppression accompanied by mTORC1 inhibition. Our preliminary data show that genetic ablation of mTORC2 in T cells significantly reverses the systemic immune activation in a mouse model of lupus. The specific aims of this proposal are, (1) To evaluate mTORC2 activity in infiltrating T cells in kidney biopsies from lupus nephritis patients; (2) To provide proof-of-principle evidence that pharmacological targeting mTORC2 benefit lupus in mouse model and to define the underlying mechanisms. The long-term objectives are to establish mTORC2 as a novel target for therapeutic treatment of lupus.
StatusFinished
Effective start/end date1/1/2012/31/21

Funding

  • Lupus Research Alliance: $300,000.00

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