# Identifying regulatory uORFs as a targetable axis for hereditary disease

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $66,558

## Abstract

Abstract (from parent grant)
The broad goal of this proposal it to computationally identify, validate, then target for therapeutic
intervention regulatory elements within the 5' untranslated regions (UTR) of protein coding genes,
known as upstream open reading frames (uORFs). In so doing, we aim to modulate the protein
output from selected genes, offering a novel, translational approach with broad potential.
uORFs are segments of 5′UTR mRNA sequences that can initiate and terminate translation
upstream of protein-coding (CDS) start codons. Rare uORFs have been shown to produce
potentially functional micro-peptides, while others affect protein expression by tuning translation
rates of downstream protein-coding sequences. Our recent work showed that uORFs exhibit
strong negative selection for preserving their start and stop codons, but not the encoded
sequence, favoring the notion that uORFs have been retained through evolution because of their
cis regulatory effect on protein gene products. Using genetic databases, we showed that variants
affecting uORF start/stop codons associate with disease phenotypes (PheWAS analysis) and
validated their expected effect on the protein (but not RNA) levels of the downstream genes.
Potential uORFs have been identified in ~50% of all human protein-coding genes, many of which
harbor more than one uORF. While blocking some uORFs decreases CDS protein output, our
unpublished data show that targeting uORFs can be used to increase CDS translation. As a
potential case for increasing protein levels, we focused on heritable pulmonary arterial
hypertension (PAH), a fatal condition with no current cure, most commonly driven by BMPR2
haploinsufficiency. By blocking a BMPR2 uORF, we were able to increase BMPR2 protein levels
by up to 220%. Based on our published and unpublished results we propose an integrative set of
computational and experimental approaches to systematically detect, prioritize, validate and
target uORFs for therapeutic intervention, focusing on genes associated with haploinsufficiency
and ASOs as an intervention.

## Key facts

- **NIH application ID:** 11100382
- **Project number:** 3R01GM147739-03S1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Yoseph Barash
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $66,558
- **Award type:** 3
- **Project period:** 2022-09-23 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11100382

## Citation

> US National Institutes of Health, RePORTER application 11100382, Identifying regulatory uORFs as a targetable axis for hereditary disease (3R01GM147739-03S1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/11100382. Licensed CC0.

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