# MicroRNA directed pathway discovery in allergy and asthma

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $403,750

## Abstract

PROJECT SUMMARY
 Asthma is a highly prevalent chronic inflammatory airway disease with tight genetic and mechanistic links to
allergy. Hyperproduction of antibodies of the IgE isotype is a hallmark feature of allergy and the “Th2 high”
allergic asthma endotype. IgE is produced when B cells undergo class switch recombination (CSR) and
differentiate into antibody secreting plasma cells. Secreted IgE arms mast cells and basophils to release
inflammatory mediators in response to allergen exposure, fueling both acute anaphylactic responses and
chronic inflammation. A therapeutic antibody targeting IgE reduces asthma symptoms and exacerbations in
many patients with moderate to severe persistent disease. Understanding the molecular programming that
underlies IgE production may lead to novel and more effective approaches for the prevention and treatment of
allergy and asthma.
 MicroRNAs (miRNAs) are tiny regulators of gene expression that mediate powerful biological effects
through their concerted action on networks of target mRNAs. Over 100 distinct miRNAs are expressed in B
cells, but critical physiological functions have been assigned to few, so far. Several years ago, we developed a
robust screening platform for uncovering miRNA regulators of helper T cell differentiation. We have now fully
adapted this system for use in primary B cells and used it to uncover miRNA regulators of CSR and IgE
production, including miR-221/222, miR-155 and several other strong novel candidates for further study.
 The central objective of this proposal is to leverage B cell miRNA:target networks to discover genes and
pathways involved in the development and pathogenesis of allergy and asthma. Guided by strong preliminary
data, we will rigorously interrogate the function of miR-221/222 and select other miRNA families implicated in
IgE production using in vitro culture systems and mouse aeroallergen exposure models of asthma. We will
perform comparative Ago2 HITS-CLIP on B cells and combine this biochemical approach with gene expression
and computational analyses to generate a map of experimentally defined functional miRNA binding sites
throughout the B cell transcriptome. These data will facilitate miRNA-directed discovery of genes and pathways
involved in IgE production. Based on preliminary data, we have selected the transcription factor Foxp1 and two
other novel miR-221/222 targets to be the first subjects of detailed analysis, taking advantage of existing
mutant mice, small molecule inhibitors, and CRISPR/Cas9 genome editing protocols in mouse and human
primary B cells. We expect the proposed research to generate novel insights about allergic sensitization and
the immunopathogenesis of allergic asthma. In addition, our studies will advance our fundamental
understanding of the network properties of miRNA regulation of gene expression and cell behavior.

## Key facts

- **NIH application ID:** 10072457
- **Project number:** 2R01HL109102-10
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Karl Mark Ansel
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $403,750
- **Award type:** 2
- **Project period:** 2011-08-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10072457

## Citation

> US National Institutes of Health, RePORTER application 10072457, MicroRNA directed pathway discovery in allergy and asthma (2R01HL109102-10). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10072457. Licensed CC0.

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