# Identifying regulatory uORFs as a targetable axis for hereditary disease

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2022 · $394,453

## Abstract

Abstract
The aim of this grant is to 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, that we will first test in the context of animal models of hereditary diseases. To
achieve the goals of our integrative MultiPI R01, we will leverage the expertise of both our labs spanning
computational modeling, genomics, genetics, RNA biology, molecular biology, and animal work. In Aim 1 we
will combine large genomic and genetic datasets including gnomAD, the PennMedicine BioBank, and the
UKBioBank to systematically identify functional uORFs and prioritize those for validation. The resulting
database of human uORFs will be made publicly available and widely accessible as a user-friendly web-tool.
Predicted regulatory uORFs suggested by the Aim 1 pipeline will be fed into the experimental Aims 2 and 3. In
Aim 2 we will validate the high-priority uORF targets using luciferase assays and in Aim 3 we will test the
modulation of these uORFs as a potential for therapeutic intervention. The results of Aims 2 and 3 will be fed
back to the pipeline of Aim1 to improve prioritization of future uORFs. Overall, we expect the resources and
discoveries made by this grant to shed light on the functional role of uORF and offer therapeutic avenues for
several hereditary diseases.

## Key facts

- **NIH application ID:** 10504131
- **Project number:** 1R01GM147739-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Yoseph Barash
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $394,453
- **Award type:** 1
- **Project period:** 2022-09-23 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10504131

## Citation

> US National Institutes of Health, RePORTER application 10504131, Identifying regulatory uORFs as a targetable axis for hereditary disease (1R01GM147739-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10504131. Licensed CC0.

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