Project description
Understanding alternative splicing in beta cell dysfunction
It is estimated that 10 % of the global population suffers from diabetes, resulting from the destruction or functional failure of insulin-producing pancreatic beta cells. Although the genetic control of beta cells is well documented, little is known about how alternative splicing contributes to their function and diversity. Supported by the Marie Skłodowska-Curie Actions programme, the BetaSpReg project will address this knowledge gap, aiming to identify the mechanisms by which hnRNP splicing regulators affect insulin secretion, development and stress resistance of beta cells. Furthermore, it will investigate the use of splice-switching oligonucleotides as therapeutic strategies to modulate these regulatory pathways and test them in primary human islets from type 2 diabetes donors.
Objective
Diabetes mellitus affects over 500 million people worldwide and arises from the progressive loss of functional insulin-producing beta cells. While transcriptional and epigenetic regulation of beta cells has been studied extensively, the role of alternative splicing, a fundamental mechanism that expands transcriptome and proteome diversity, remains poorly understood in this context. The BetaSpReg project aims to uncover how splicing regulators of the hnRNP family control beta cell development, function, and stress resilience, and to explore splice-switching oligonucleotides (SSOs) as a novel therapeutic strategy.
Using human induced pluripotent stem cell-derived islets (SC-islets) and advanced CRISPR genome editing, I will generate precise knockout, inducible, and rescue models for hnRNPA2B1 and hnRNPM, two strong candidate regulators of beta cell splicing. I will combine functional assays, multi-omics profiling, and RNA immunoprecipitation followed by sequencing (RIP-seq) to define hnRNP-regulated splicing networks under basal and diabetogenic stress conditions. To increase the translational relevance, I will test SSOs targeting dysregulated splicing events in primary human islets from type 2 diabetes donors.
By delivering the first mechanistic map of splicing regulation in human beta cells, BetaSpReg will expand our understanding of alternative splicing in diabetes, establish proof-of-concept for splicing modulation as therapy, and provide a foundation for RNA-based precision medicine in metabolic disease.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences biochemistry biomolecules proteins proteomics
- medical and health sciences medical biotechnology genetic engineering gene therapy
- medical and health sciences clinical medicine endocrinology diabetes
- natural sciences biological sciences genetics RNA transcriptomes
- medical and health sciences health sciences personalized medicine
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Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
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HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA)
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HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European Fellowships
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(opens in new window) HORIZON-MSCA-2025-PF
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85764 Neuherberg
Germany
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