Project Abstracts - New Investigators

Start Date: May 1, 2026

NIH HIRN Gateway Investigator Award Recipient 

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Abstract

Type 1 diabetes (T1D) is characterized by selective autoimmune-mediated destruction of insulin-producing pancreatic beta cells. While genetic studies have identified numerous risk loci explaining a substantial proportion of disease susceptibility, translating these findings into actionable biological mechanisms and therapeutic strategies remains a major challenge. To date, most research advances have focused on T cell–mediated autoimmunity, leading to therapies that delay disease onset in a subset of individuals. However, incomplete and variable responses highlight pathological mechanisms beyond immune cell dysfunction.

Emerging evidence suggests that beta cells are not passive targets but active contributors to their own destruction. In particular, dysregulation of mRNA translation can impose proteotoxic and endoplasmic reticulum (ER) stress, compromising beta-cell survival while generating neoantigens that enhance beta-cell immunogenicity and immune attack. Building on this concept, our work integrates genetic and functional genomic data to define how T1D risk variation dysregulates mRNA translational control, leading to beta-cell dysfunction and destruction. We have identified dysregulation of the ribosomal protein RPS26 as a genetically mediated risk factor for T1D. RPS26 is known to influence mRNA translation fidelity and context-dependent specialization of translation, particularly for transcripts with features similar to insulin mRNA, suggesting a mechanism for altered protein synthesis, neoantigen generation, and cellular stress in beta cells.

We hypothesize that genetically driven upregulation of RPS26 disrupts translation fidelity and efficiency in beta cells, leading to impaired protein homeostasis, increased cellular stress, and enhanced immunogenicity. To test this, we will combine human genetic analyses with experimental beta-cell models to examine how modulation of RPS26 expression and T1D-associated variants affect translation dynamics, beta-cell health, and immune recognition. In parallel, we will evaluate the impact of beta cell–specific Rps26 modulation in autoimmune-prone mouse models and assess genetic associations with beta-cell function in human cohorts.

This work aims to define a unified mechanism linking genetic risk to beta-cell dysfunction and immune targeting in T1D. By uncovering how translational dysregulation drives both beta-cell stress and immunogenicity, our studies may reveal new therapeutic opportunities to preserve beta-cell function and improve outcomes for individuals at risk for or living with T1D.