# Molecular and Cellular Dissection of miRNAs in Controlling Allergic Airway Inflammation in Mice

> **NIH VA I01** · MICHAEL E DEBAKEY VA MEDICAL CENTER · 2022 · —

## Abstract

The long-term objective of our laboratory is to understand the underlying molecular and genetic causes for
chronic allergic airway inflammation or asthma to improve therapeutic approaches. The specific objective of
this application is to dissect microRNA (miRNA)-dependent inflammatory pathways in dendritic cells (DCs) and
CD4+ T cells that modulate murine allergic airway disease to fungal allergens. Asthma is a major rising global
health threat that disproportionately affects combat veterans. We showed that patients with asthma often have
evidence of airway mycosis, defined as detection of fungi in airway secretions in association with specific
biomarkers (e.g. IgE or TH2 cells) reactive to one or more fungi. Our laboratory and others have shown that
fungal proteinases and fungal spores drive asthma-like airway disease in mice. Airway epithelial cells express
pattern recognition receptors (PRRs) for foreign antigens (e.g. TLRs, C-type lectin, and protease-activated
receptors) and important for conventional dendritic cell (cDC) activation and initiation of allergic CD4+ type 2
cell (TH2) and TH17 cell-dependent airway inflammation, IgE production, and airway hyperresponsiveness
(AHR), collectively termed allergic airway disease. We and others have shown the requirement of TH2 cells
and DC in the pathogenesis of allergic airway disease. We employed murine models of chronic allergic airway
inflammation, and detected aberrant expression of let-7 miRNA family in lung, CD4+ T cells and CD11c+ DCs.
Specifically, the expression of let-7b and let-7c (let-7bc-cluster) is reduced in sorted lung CD4+ T cells and
enhanced in CD11c+ antigen presenting cells (APCs) of mice with chronic allergic airway disease. Moreover,
mice that lack the let-7bc-cluster globally or specifically in CD4+ T cells or CD11c+ APCs show blunted TH2
responses and allergic disease. On the other hand enforced expression of let-7 specifically in CD4+ T cells
enhances fungus-induced allergic airway disease. The let-7b and let-7c members only account for only 9% of
total let-7 activity in lymphocytes and myeloid cells suggesting that let-7bc cluster critically determines gene
expression of CD4+ T cells and DCs that drive allergic sensitization to Aspergillus niger. Our central hypothesis
therefore states that the let-7 family modulates allergic airway disease severity and orchestrates activation of
cDCs and TH2 responses. We will address this hypothesis through the following Specific Aims: 1) Elucidate
the CD4+ T cell intrinsic requirement of the let-7bc-cluster in pathogenesis of allergic airway disease.
Hypothesis: The let-7bc-cluster regulates target gene expression in CD4+ T cells and controls TH2 lung
inflammation and allergic airway disease. 2) Determine the role of let-7bc-cluster in DC-mediated control of
allergic airway inflammation. Hypothesis: Induction of let-7bc-cluster expression in asthmatic lung cDCs directs
molecular programming of TH2 driven pulmonary allergic inflammatio...

## Key facts

- **NIH application ID:** 10477187
- **Project number:** 5I01BX004828-03
- **Recipient organization:** MICHAEL E DEBAKEY VA MEDICAL CENTER
- **Principal Investigator:** DAVID B CORRY
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2020-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10477187

## Citation

> US National Institutes of Health, RePORTER application 10477187, Molecular and Cellular Dissection of miRNAs in Controlling Allergic Airway Inflammation in Mice (5I01BX004828-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10477187. Licensed CC0.

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