# Decoding Mechanisms of Nonsense-mediated mRNA Decay through Alternative Splicing

> **NIH NIH R35** · UNIV OF ARKANSAS FOR MED SCIS · 2024 · $376,670

## Abstract

SUMMARY
The human genome preserves a strict regulation of gene expression to maintain physiological integrity. RNA
processing plays a key central role in this regulation and has drawn significant attention in recent times due to
its implications for a wide breadth of diseases. Alternative splicing (AS) can encode different protein isoforms
from the same gene to support rapidly changing biological processes. AS often generates erroneous mRNAs
with a premature translation termination codon, which are selectively degraded by nonsense-mediated mRNA
decay (NMD) to safeguard the generation of defective proteins. This coordinated action is termed as AS-NMD.
In humans, ~95% of genes undergo AS, among which ~33% are targets of AS-NMD, suggesting that it is not
merely noise. Substantial evidence demonstrated that AS-NMD evolved as a powerful mechanism to regulate
gene expression in normal physiology and is often fine-tuned in a developmental stage-specific or tissue-specific
manner. Growing evidence suggests that AS-NMD is frequently dysregulated (induced or suppressed) and is
the root of many human maladies. Why certain genes in certain tissues or diseases are susceptible to differential
or aberrant AS-NMD regulation remains an unresolved mystery. Therefore, elucidating the regulation of AS-
NMD is crucial to understanding this vital mechanism in normal physiology and diseases, which will redefine
therapeutic strategy and significantly impact clinical outcomes. We recently showed that AS-NMD is induced in
splicing factor mutated hematopoietic defects. In contrast, AS-NMD is suppressed in splicing factor
overexpressed diseases (such as cardiac and liver dysfunction, brain and developmental abnormalities,
diabetes, lupus, and neoplasia). These provide excellent model systems to systematically identify positive and
negative effectors and underlying mechanisms of differential AS-NMD regulation. We will characterize the AS-
NMD regulation in normal cells and its misregulation (induction and suppression) in disease-specific model cells.
We will define cis-acting RNA codes that regulate AS-NMD, characterize trans-acting protein networks and their
dynamic interactions with RNA in the AS-NMD pathway, and delineate tissue-specific or disease-specific
mechanisms. Finally, we will develop tools to manipulate AS-NMD errors using oligonucleotide-based
pharmacology as a therapeutic approach. Completion of these studies will connect the missing puzzles in the
AS-NMD regulation, answer how an evolutionarily conserved surveillance mechanism can be exploited to turn
on pathological maladies, and develop a commonly approached innovative molecular technology to correct AS-
NMD errors applicable to a range of human diseases.

## Key facts

- **NIH application ID:** 10941535
- **Project number:** 1R35GM154991-01
- **Recipient organization:** UNIV OF ARKANSAS FOR MED SCIS
- **Principal Investigator:** MOHAMMAD ALINOOR RAHMAN
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $376,670
- **Award type:** 1
- **Project period:** 2024-07-08 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10941535

## Citation

> US National Institutes of Health, RePORTER application 10941535, Decoding Mechanisms of Nonsense-mediated mRNA Decay through Alternative Splicing (1R35GM154991-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10941535. Licensed CC0.

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