# Understanding the NMD regulatory path from genetic variation to phenotypes

> **NIH NIH R01** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2021 · $323,291

## Abstract

PROJECT SUMMARY
There are fundamental gaps in our understanding of the regulatory mechanisms of nonsense-
mediated mRNA decay (NMD). Originally conceived as a quality-control checkpoint to recognize
and degrade aberrant transcripts, NMD has become appreciated as a post-transcriptional gene
regulation mechanism to fine-tune expression of many non-aberrant endogenous mRNAs.
However, despite a plethora of biochemical characterization on the NMD pathway, the
mechanism of NMD regulation and the criteria for NMD target selection are poorly understood.
 Our long-term goal is to develop computational methods to discover the principles of gene
expression regulation and explore how variations or defects in gene regulation cause
phenotypic variation or disease. The overall objective of this application is to elucidate the
context-dependent NMD regulation of individual genes through genetical genomics. Genetic
variants associated with changes in gene expression (expression quantitative trait loci, eQTLs)
are being catalogued in increasingly large-scale human studies, such as the Genotype-Tissue
Expression (GTEx) project. We will take advantage of this unprecedented resource to dissect
NMD control and to discover NMD regulatory rules in a systematic and unbiased manner.
Traditional biochemical and molecular approaches are essential to deciphering NMD
mechanism but are slow in progress with intrinsic limitations. Genetical genomics will provide a
fresh view and has great promise to uncover new regulatory rules of NMD. We will develop
novel statistical and computational methods tailored to the analysis of NMD regulation. These
methods can also be broadly applied to studies of other regulatory variants. Our long-standing
expertise in transcriptomics analysis, eQTL analysis, and NMD regulation places us in a unique
position to accomplish the proposed project.
 The proposed methods meet the analysis challenges arising from transcriptomics, eQTL
mapping, and RNA biology. The completion of this project will vertically advance and expand
our understanding of how NMD regulates gene expression. Ultimately, such knowledge has the
potential to develop NMD-based preventive and therapeutic interventions.

## Key facts

- **NIH application ID:** 10149360
- **Project number:** 5R01GM137428-02
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Liang Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $323,291
- **Award type:** 5
- **Project period:** 2020-05-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10149360

## Citation

> US National Institutes of Health, RePORTER application 10149360, Understanding the NMD regulatory path from genetic variation to phenotypes (5R01GM137428-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10149360. Licensed CC0.

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