# Post-transcriptional control of gene expression by the mTORC1 signaling pathway

> **NIH NIH R35** · YALE UNIVERSITY · 2024 · $418,750

## Abstract

Project summary
The translation of mRNAs into protein is a fundamental step in gene expression that is regulated
by diverse cellular signals. How these regulatory mechanisms are used to orchestrate changes
in gene expression and cellular function remains poorly understood. We have been studying this
question through examination of the mTOR Complex 1 (mTORC1) signaling pathway, a master
regulator of growth throughout eukaryotes. This pathway senses nutrient signals and responds
by activating the cellular biosynthesis machinery to drive growth. Deregulation is linked to
human diseases ranging from cancers to neurological disorders. A central function of mTORC1
is to activate “cap-dependent” translation through the eIF4F translation factor. Over the past five
years, my laboratory has shown how this mechanism is used to control the translation and
stability of hundreds of mRNAs with essential growth functions, including nearly all ribosomal
proteins. More recently, we identified hundreds of mRNAs that are hyper-dependent on cap-
dependent translation for unknown reasons and thousands that access “cap-independent”
initiation mechanisms that remain unclear. Going forward, our research program seeks to
answer several basic questions that emerge from these observations. First, what mRNA
features define dependence on cap-dependent and cap-independent translation mechanisms
and how are they detected? Second, how does regulation of cap-dependent translation trigger
global and specific changes in mRNA stability? Third, how does variation in the structure of the
transcriptome (e.g. alternative promoters) specialize the post-transcriptional regulation of
mRNAs across tissues in vivo? We propose to tackle these questions using a combination of
transcriptomic strategies, massively parallel reporter assays, and bioinformatic analyses in cells
and in vivo that we have established over the last five years. Our ultimate goal is to fully
understand the molecular systems that control growth-regulated gene expression, establish
their function in the cellular growth process, and link their function to growth-related physiology.
We expect these efforts to yield insights into basic principles of gene regulation that are used to
adapt cells and organisms to changing nutrient availability.

## Key facts

- **NIH application ID:** 10765415
- **Project number:** 1R35GM152167-01
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Carson Cornell Thoreen
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $418,750
- **Award type:** 1
- **Project period:** 2024-08-08 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10765415

## Citation

> US National Institutes of Health, RePORTER application 10765415, Post-transcriptional control of gene expression by the mTORC1 signaling pathway (1R35GM152167-01). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10765415. Licensed CC0.

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