# Alternative RNA splicing events contribute to the onset of islet dysfunction in T1D

> **NIH NIH U01** · UNIVERSITY OF COLORADO DENVER · 2020 · $750,874

## Abstract

Type 1 diabetes mellitus (T1D) is a chronic disease resulting from the autoimmune destruction of insulin-
producing pancreatic b cells. Although T1D is primarily associated with a dysfunctional immune response, recent
genome-wide association studies (GWAS) have determined that a large number of T1D associated genes are
expressed in pancreatic b cells. Currently, there are many ongoing studies to identify the underlying molecular
mechanisms that impact b cell dysfunction in T1D, with hopes that this knowledge can be used to develop novel
biomarkers and preventive disease therapies. We hypothesize that altered RNA splicing events contribute
to b cell dysfunction and potentially contribute to the formation of immunogenic protein isoforms to
trigger T1D. Recently, our ability to perform genome wide RNA sequencing has revealed the complexity of the
transcriptome and has provided significant insight into the transcriptomic modifications that occur during
physiological and pathophysiological processes. In particular, there is a growing appreciation for the role of
alternative splicing in many biological processes. The biological importance of alternative splicing has been
further emphasized by the large number of human diseases caused by mutations that affect the splicing program.
In the pancreas, a recent study showed considerable dysregulation of RNA binding proteins (RBPs) and aberrant
mRNA splicing in islets derived from type 2 diabetic patients compared to healthy controls. While these studies
have illustrated the existence of alternative splicing networks in the pancreas, and identified some of the enzymes
involved in the regulation of alternative splicing, there has been relatively little demonstration of the functional
consequences of alternative splicing events and how they may contribute to T1D pathogenesis. We propose
studies to investigate the physiological relevance of alternative splicing events in b cells. Importantly, given the
heterogeneous nature of b cell destruction in T1D, we will assess cell specific altered RNA splicing products at
the single cell sequencing level, and in situ at a single cell and near single cell resolution to fully understand the
potentially cell-specific functional consequences of altered spliced variants. Furthermore, we will identify
potentially novel protein products that arise due to the alternative splicing events. To accomplish our goals, we
propose the following specific aims: Aim 1. Use novel RNA sequencing technologies to identify conserved
alternatively spliced transcripts in mouse and human T1D islet samples; Aim 2. Determine the localization of
candidate RNA isoforms to individual human islet cells using fliFISH as a high accuracy smFISH approach that
localizes individual transcripts with 20-30 nm resolution using STORM microscopy; Aim 3. Use advanced
proteomics and innovative computational approaches to identify candidate novel protein products generated
from alternative spliced transcripts in T1D ...

## Key facts

- **NIH application ID:** 10136206
- **Project number:** 1U01DK127505-01
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Ernesto Satoshi Nakayasu
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $750,874
- **Award type:** 1
- **Project period:** 2020-09-15 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10136206

## Citation

> US National Institutes of Health, RePORTER application 10136206, Alternative RNA splicing events contribute to the onset of islet dysfunction in T1D (1U01DK127505-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10136206. Licensed CC0.

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