# Mechanism of Protein Synthesis and Translational Control

> **NIH NIH R35** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2024 · $359,952

## Abstract

Project Summary
 Our research program focuses on the mechanism of eukaryotic protein synthesis and translational
control. The two projects we are currently studying are: (1) the mechanism of translational control by the fragile
X mental retardation protein (FMRP), and (2) the mechanism of translation initiation on influenza A virus (IAV)
mRNAs. Fragile X syndrome is a disease that afflicts about 100,000 Americans and about 3 million people
worldwide, resulting in intellectual disability, childhood seizures, and autistic behavior in the patients. The
disease is caused by the transcriptional silencing of the fragile X mental retardation 1 gene (FMR1). FMR1 gene
codes for an RNA-binding protein, FMRP, which is highly expressed in the brain and is essential for the normal
development of the brain. Mammals have two autosomal paralogs of FMRP designated as fragile X related 1
and 2 (FXR1 and FXR2) proteins. FMRP, FXR1 and FXR2 have been implicated in regulating the translation of
several mRNAs. However, the precise mechanism by which these proteins regulate the expression of these
mRNAs is unknown. The goal of the first project is to understand the molecular mechanism underlying the
regulation of protein synthesis by FMRP, FXR1 and FXR2. We will use a robust in vitro translation system,
biochemical techniques and quantitative biophysical methods to significantly advance our understanding of the
molecular mechanism used by FMRP, FXR1 and FXR2 to regulate protein synthesis. Results of these studies
will provide useful insights in identifying potential drug targets to treat fragile X syndrome.
 The goal of the second project is to investigate the mechanism of translation initiation by IAV mRNAs.
IAV is responsible for several thousand deaths annually and is a severe threat to global public health. We have
new data that indicate that IAV mRNAs may use a non-canonical mechanism of translation initiation. Our studies
show that poly A binding protein 1 (PABP1) binds to the highly conserved sequences present in the 5’-UTR of
IAV mRNAs. Additionally, we show that the translation of the IAV mRNA is more resistant to the inactivation of
eukaryotic initiation factor 4E (eIF4E) compared to a control mRNA. We hypothesize that the recruitment of
PABP1 to the viral 5’-UTRs tethers eIF4G and promote the assembly of the translation initiation complex in an
eIF4E-independent manner. This may favor the translation of IAV mRNAs under cellular stress conditions in the
cell, which is known to reduce the activity of eIF4E. We will determine whether the binding of PABP1 to the 5’-
UTR of IAV mRNAs is essential for translation initiation and the viral cycle using in vitro techniques and cellular
IAV infection studies. Our research will lead to fundamental new knowledge about the process of translation
initiation on IAV mRNAs, which could help in the development of new antiviral drugs.

## Key facts

- **NIH application ID:** 10906006
- **Project number:** 5R35GM141864-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** SIMPSON JOSEPH
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $359,952
- **Award type:** 5
- **Project period:** 2021-06-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10906006

## Citation

> US National Institutes of Health, RePORTER application 10906006, Mechanism of Protein Synthesis and Translational Control (5R35GM141864-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10906006. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*