# Dissecting the regulation of RNA sensing in innate immunity

> **NIH NIH R00** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2021 · $249,000

## Abstract

SUMMARY
The discovery of RNA interference and related small RNA pathways has revolutionized molecular biology and
bears potential for new generations of therapeutics. Endogenous small RNAs such as microRNAs (miRNAs)
collectively regulate the majority of the human transcriptome, and control important aspects of spatio-temporal
development. Dysregulation of the miRNA pathway therefore directly contributes to developmental defects
and tumorigenesis. Another group of small RNAs call Piwi-interacting RNAs (piRNAs) are often active during
germline development, and preserve genome integrity by silencing selfish elements such as transposons.
Despite of the progress made on understanding small RNA pathways, we still lack a clear picture of how each
step of the pathway is carried out. Biochemical and structural characterization of the molecular machineries
that promote these steps will represent major advances for the field.
 I have a long-standing interest in small RNA pathways. During my graduate studies at Princeton
University with Dr. Laura Landweber, which were funded by a pre-doctoral fellowship by the Department of
Defense Breast Cancer Research Program, I uncovered an unknown function for piRNAs to protect DNA
against loss during genome rearrangement in Oxytricha. This was one of the first studies to show “self”
recognition by piRNAs, and overturned the dogma that piRNAs only target RNA for repression or DNA for
deletion. Then, as a post-doctoral fellow in the laboratory of Dr. David Bartel at the Whitehead Institute, I
studied the miRNA pathway, which is the small RNA pathway that dominates in most human cells.
Specifically, I identified determinants of primary miRNAs (pri-miRNAs, the precursors of miRNAs) that allow for
their efficient processing by the Microprocessor complex, and demonstrated rational, de novo design of
artificial miRNA genes. This work was funded by the Damon Runyon Cancer Research fellowship.
 My long-term goal is to understand how RNA-protein interactions work, with a special focus on small
RNA pathways. I would like to pursue this exciting topic as the leader of a research group in an academic
institution. To achieve this goal, the overall objectives of this application are to obtain training in protein
biochemistry and single-particle cryo-electron microscopy (cryo-EM). This valuable training and experience
will lay a solid foundation for me to launch my independent research on RNA-protein complexes.
 The work proposed here comprises two aims. In Aim 1, which will be completed during the mentored
phase, I will leverage my knowledge of pri-miRNAs, the Microprocessor substrate, and harness recent
development of cryo-EM, to solve the structure of Microprocessor bound with pri-miRNA, which will provide
critical insights into how this complex recognizes its substrate and accurately positions the cleavage. I have
already demonstrated that a novel, RNA-based purification strategy allowed the assembly of homogeneous
Microprocessor ...

## Key facts

- **NIH application ID:** 10402427
- **Project number:** 4R00GM123230-03
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Wenwen Fang
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $249,000
- **Award type:** 4N
- **Project period:** 2017-07-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10402427

## Citation

> US National Institutes of Health, RePORTER application 10402427, Dissecting the regulation of RNA sensing in innate immunity (4R00GM123230-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10402427. Licensed CC0.

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