# Structural and Mechanistic basis for RNA Silencing

> **NIH NIH R35** · SCRIPPS RESEARCH INSTITUTE, THE · 2022 · $677,250

## Abstract

Project Summary/Abstract
Nearly every cell in the human body contains a set of programmable gene-silencing proteins named
Argonaute. The natural function of Argonaute proteins is to mediate gene-regulation by microRNAs
(miRNAs), small RNAs that contribute to cellular homeostasis during diverse physiological process, such
as stem cell maintenance, fertilization, and heart development. Human Argoanute-2 (Ago2) can also be
harnessed for experimental and therapeutic purposes through the introduction of small interfering RNAs
(siRNAs), which are bound by Ago2 and used to direct the silencing of targeted genes. The overarching
goal of this research is to understand how small RNAs are generated and used by Argonaute to silence
genes. The rational motivating this work is that improved understanding of silencing processes will
empower efforts to harness these mechanisms in a therapeutic setting and inform treatment of disease
states resulting from aberrant miRNA function. Additionally, because miRNAs contribute in many facets of
human biology, improvements in understanding function will enable researchers studying diverse aspects
of human health and disease. Major projects include: 1) determining the structure of human Dicer, the
enzyme that catalyzes the final step of miRNA biogenesis, with the goal of understanding how Dicer
mutations drive diverse and devastating forms of human cancer; 2) identifying determinants of miRNA
targeting with the goal of improving prediction of miRNA targets; 3) investigate the structure of miRNA-
induced silencing complexes with a focus on understating how liquid:liquid phase separation contributes
to gene-regulation by miRNAs; 4) establish the structural basis for mRNA cleavage by siRNAs, with the
goal of providing novel insights for rational design of therapeutic siRNAs. The combined studies are
expected to provide fundamental knowledge necessary for deciphering and controlling Argonaute-
mediated regulation of human gene expression.

## Key facts

- **NIH application ID:** 10448453
- **Project number:** 5R35GM127090-05
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** IAN JOHN MACRAE
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $677,250
- **Award type:** 5
- **Project period:** 2018-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10448453

## Citation

> US National Institutes of Health, RePORTER application 10448453, Structural and Mechanistic basis for RNA Silencing (5R35GM127090-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10448453. Licensed CC0.

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