# Investigating microRNA Function in Homeostasis, Regeneration and Cancer

> **NIH NIH R01** · SLOAN-KETTERING INST CAN RESEARCH · 2021 · $519,566

## Abstract

ABSTRACT
Precise temporal and spatial control of gene expression is essential to ensure normal development and
homeostasis and is achieved through multiple regulatory mechanisms acting at every step from gene
transcription to protein degradation. MicroRNAs (miRNAs), constitute a large class of highly conserved
regulatory short non-coding RNAs that modulate gene expression at the post-transcriptional level.
Mechanistically, miRNAs repress their targets as part of a large multicomponent ribonucleoprotein known as
the miRNA-Induced Silencing Complex (miRISC), which include Argonaute proteins (AGO) and members of the
TNRC6 family of proteins.
How miRISC assembly and activity are regulated in vivo remains poorly understood and until recently it was
tacitly assumed that miRNAs are constitutively active in all cell types. Recent work from several groups, including
ours, has challenged this assumption, revealing that assembly of the miRISC is tightly regulated in vivo, and
suggesting the possibility that in many adult tissues and in quiescent cells the bulk of miRNA-bound AGO
proteins are not bound to target mRNAs, and are not engaged in their repression.
Why many adult tissues and quiescent cells contain high levels of functionally inactive miRNAs and
whether, in addition to mitogenic cues, other perturbations—including cancer, aging, infection, and
inflammation—regulate miRISC assembly and activity are two major unanswered questions in the field
and the main focus of this grant proposal.
As a first step to address these two questions we propose a series of experiment that take advantage of a novel
genetically engineered mouse strain we have recently generated that allows to control miRISC assembly in vivo
in a temporally and spatially controlled fashion. We will use this novel mouse strain to determine the requirement
for miRISC activity during normal tissue homeostasis, in development, and during tissue regeneration (Aim 1).
In Aim 2, we will use it to directly test the hypothesis that miRISC activity is required for tumor progression and
tumor maintenance in vivo and we will determine the potential of miRISC inhibition as a novel anticancer strategy.
Finally, in Aim 3 we will take advantage of a novel mouse strain we have developed to gain mechanistic insights
into how miRNAs control these essential processes.
Successful completion of this project will greatly advance our understanding of the role of miRNA-mediated gene
repression in mammals and could lead to the development of novel anti-cancer strategies.

## Key facts

- **NIH application ID:** 10242920
- **Project number:** 5R01CA245507-02
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Andrea Ventura
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $519,566
- **Award type:** 5
- **Project period:** 2020-09-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10242920

## Citation

> US National Institutes of Health, RePORTER application 10242920, Investigating microRNA Function in Homeostasis, Regeneration and Cancer (5R01CA245507-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10242920. Licensed CC0.

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