[R03] Genetic dysregulation of mRNA translation in type 1 diabetes
Ente: National Institute of Diabetes and Digestive and Kidney Diseases
Scadenza: 2028-04-30
Importo max: 167.916 EUR
Paese: US
Descrizione
Project Summary/Abstract
Type 1 diabetes (T1D), which is characterized by T cell-mediated destruction of insulin-producing pancreatic
beta cells, has a relatively well-defined genetic architecture that explains about 50% of inter-individual
differences in disease risk. However, translating the genetic architecture into novel disease insights and
therapies has lagged behind because its molecular and cellular mechanisms are incompletely understood.
Studies have established a strong impact of T1D genetics on T cells, which supports the development of the
only FDA-approved drug for delaying T1D-onset in high-risk individuals by targeting T cells. However, majority
of individuals are non-responsive to this drug and/or develop disease regardless. The selective destruction of
beta cells but no other endocrine cells that are embedded with beta cells in the islets implicates intrinsic beta-
cell biology as a driver of T1D development. An emerging mechanism causing beta-cell destruction is
noncanonical mRNA translation that generates neoantigens that act as autoantigens to invoke destruction by T
cells. Accordingly, studies have elegantly demonstrated that insulin gene (INS) variation contributes to T1D risk
by modulating the fidelity and efficiency of insulin mRNA translation in beta cells. In pursuit of our efforts to
understand how genetics affect beta-cell biology and contribute to T1D, we overlayed T1D risk variants with
variants that regulate gene expression and discovered genetic upregulation of RPS26 expression levels in
human beta cells causally contributes to T1D risk. We further found that RPS26 expression is upregulated in
beta cells from patients with T1D compared to control individuals. RPS26 is involved in mRNA translation and
prior studies demonstrated that RPS26 protein can directly bind to certain mRNAs with features similar to that
of insulin mRNA and orchestrate noncanonical translation. For instance, RPS26 has been shown to promote
noncanonical translation of neurotoxic FMR1 mRNA bearing polymorphisms that are similar to those in the
insulin mRNA. We herein hypothesize that genetic regulation of upregulation of RPS26 expression dysregulate
translation efficiency and fidelity in beta cells, which impairs their vitality while enhancing immunogenicity in
T1D. We will use genetic approaches to downregulate RPS26 expression and to induce T1D-related point
mutations respectively in human beta cells and surrogate beta cells to understand the impact on beta-cell
vitality, translation efficiency and fidelity, and immunogenicity. We will also use recombinant adeno-associated
virus to specifically knockdown Rps26 in beta cells of autoimmune diabetes-prone NOD/ShiLtJ mice and
investigate the impact on diabetes incidence. We will investigate the correlation between RPS26 genetic
variation and markers of functional beta-cell mass in patients with T1D using the UK Biobank and the
DCCT/EDIC study datasets. The findings from these studies are expected
Istituzione: YALE UNIVERSITY
PI: David A Alagpulinsa
Progetto: 1R03DK147560-01
Settori: National Institute of Diabetes and Digestive and Kidney Diseases
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