Friday, May 9, 2025
5/9/2025
Role of mTORC1 signaling in type 1 diabetes - Project Summary/Abstract Type 1 diabetes (T1D) is a devastating disease with increased incidence in the world. Proposed therapeutic therapies for this disease have focused on preservation of beta cells and immunomodulation. The mTOR complex 1 (mTORC1), a nutrient sensor, regulates beta cell mass and proliferation by acting on S6K and 4E- BPs, two major downstream targets of mTORC1. 4E-BPs are hyperphosphorylated by mTORC1 causing their release from eIF4E and promotion of translation initiation. Activation of 4E-BP2/eIF4E pathway by 4E-BP2 deletion induces beta cell expansion and proliferation by upregulation of IRS2 levels. In addition to beta cells, mTORC1/4E-BP axis is also crucial for the regulation of adaptive immunity. Preliminary studies suggest that 4E- BP2 deletion has prosurvival effects for the beta cell in vitro against the cytotoxic effects of pro-inflammatory cytokines, a cause of beta cell demise in T1D. Using a newly generated global 4E-BP2 deficient mice in the NOD background (4E-BP2KONOD), preliminary studies showed that 90% of male (not female) mice were protected from the development of T1D by preserving beta cell mass. In addition, adoptive transfer studies into NOD.scid mice showed that mice that received splenocytes from 4E-BP2KONOD mice developed significantly less diabetes than controls that received splenocytes from WT mice. This suggests that inhibition of 4E-BP2/eIF4E interaction could be a promising therapeutic strategy for T1D by potentially preserving functional beta cells, reduction in autoimmune injury and enhancing beta cell regeneration. However, how 4E-BP2 deletion protects beta cells from autoimmune injury and induces immunomodulatory effects and the potential sexual dimorphism of this phenotype is unknown. Our hypothesis is that 4E-BP2 deletion reverses T1D by two distinct mechanisms: 1. . Augmenting survival and conserving beta cell function in a T1D inflammatory environment, and 2. modulating the ability of lymphocytes to mount an immune response. The following aims will test this hypothesis: Aim 1. To determine the contribution and molecular mechanisms mediated by 4E-BP2 deletion on beta cell survival and function in the context of T1D and Aim 2. To uncover how 4E-BP2 deletion induces immunomodulatory effects to protect from T1D. In addition, studies assessing the contribution of beta cells or immune system in the gender dimorphic phenotype of diabetes protection will complement these aims. The proposed studies will fill an important knowledge gap by providing insights into the 4E-BP2/eIF4E activation as a pharmacological target for T1D treatment. Such results will have a positive impact because this target will serve as a platform for designing novel therapeutic strategies to expand drug development for diabetes.
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