# Stress induced changes to the human beta cell proteome

> **NIH NIH R21** · UNIVERSITY OF COLORADO DENVER · 2020 · $194,375

## Abstract

Type 1 diabetes (T1D) is an autoimmune disease that results in life-long insulin insufficiency, causes
significant increases in morbidity and mortality, and is responsible for considerable social and economic
costs. Thus, there is an urgent need for durable therapies that can prevent, arrest, or if possible reverse, the
ß-cell loss that leads to T1D. Unfortunately, at present several factors are impeding progress towards a
"true" cure. Foremost is the fact that the precise etiology of T1D in humans is still incompletely understood.
This is compounded by a paucity of robust mechanistic biomarkers that can accurately reflect the current
disease status in an individual patient. These are the critical gaps that our proposal seeks to address.
Recent studies suggest a critical role for target tissues, including pancreatic ß cells, in initiating and/or
propagating an autoimmune attack, and thus unwittingly contributing to their own demise. How could this
happen? The central hypothesis is that ß cells, which are specialized to produce large quantities of insulin,
are particularly sensitive to external factors that trigger cellular stress. Normal homeostatic responses to
stress include both transcriptional and translational reprogramming. However, a likely consequence of this
is the generation of polypeptides not normally present in ß cells that can be sources of cryptic neo-epitopes
for autoreactive T cells. While several previous studies have examined the effects of cytokine exposure on
human ß cells and detected changes in gene expression and splicing events, corresponding data on
translational reprogramming is largely absent. Studies of protective immunity have shown that CD8+ T
cells recognizing epitopes from non-canonical open reading frames (ORFs) are especially important in host
responses to viruses, raising the possibility that they may also play a key role in autoimmunity. The primary
goal of this proposal, therefore, is to define the unique spectrum of “cryptic” translation products generated
by stressed human ß cells (the “Criptome”), and determine its potential as a source of pathogenic neo-
epitopes. Three specific aims are proposed. First, we will determine the human ß cell “Criptome” by
ribosome profiling, using ribosome protected mRNA isolated from an immortalized human ß cell line, human
pluripotent stem cell (hPSC) derived ß cells, and cadaveric human islets, at baseline and following exposure
to cytokines. Second, we will validate our data using PUNCH-P, a complementary proteomics approach that
uses mass spectrometry to analyze nascent polypeptides released from isolated polysomes by puromycin.
Third, the newly identified cryptic ORFs will be interrogated for potential HLA-A2:01 epitopes, and the
immunogenicity of the top candidates assessed using transgenic HLA-A2+ mice. If successful our rigorous
approach will define a comprehensive ß cell translatome and CRiPtome, and identify novel
biomarkers of human T1D, providing important new i...

## Key facts

- **NIH application ID:** 9850537
- **Project number:** 5R21AI140044-02
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** HOWARD W DAVIDSON
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $194,375
- **Award type:** 5
- **Project period:** 2019-01-15 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9850537

## Citation

> US National Institutes of Health, RePORTER application 9850537, Stress induced changes to the human beta cell proteome (5R21AI140044-02). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9850537. Licensed CC0.

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