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NOBEL PRIZE 2026

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NIHNATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASESR01

Lipotoxicity and Maintenance of Metabolic Health

Active
Institution
JOSLIN DIABETES CENTER, MA
Principal investigator
Jean E. Schaffer
Funding
$595K
Duration
2023–2027
Open portfolio

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Abstract

ABSTRACT Lipotoxicity is an important mechanism of complications in type 2 diabetes, including non-alcoholic fatty liver disease (NAFLD). Through a genetic screen, we discovered that loss of small nucleolar RNAs (snoRNAs) embedded within introns of the ribosomal protein L13a (Rpl13a) locus confers resistance to lipotoxicity in a cell culture model. The four Rpl13a snoRNAs, SNORD32A, SNORD33, SNORD34, and SNORD35A, guide 2¢-O- methyl nucleotide modifications at five sites on nascent 18S and 28S ribosomal RNAs that lie in close proximity to key functional centers of the ribosome structure. This study will test the hypothesis that knockout of Rpl13a snoRNAs protects from lipotoxic tissue damage in a mouse model of high fat diet-induced NAFLD. We will define the mechanistic links among snoRNA abundance, mRNA translation, and dietary nutrient exposures. Findings from this work will provide new insights into the pathophysiology of NAFLD and other diseases of lipid overload and have the potential to identify new therapeutic targets for treatment of metabolic diseases.

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R01NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASESNutrition and Metabolism in Health and Disease Study Section[NMHD]ribosomalnucleolarnafldgenetic screenrnasmechanistic linksmethylmrna translation

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