# Cellular crosstalk in the maintenance of lung epithelial homeostasis

> **NIH NIH F32** · BROAD INSTITUTE, INC. · 2020 · $64,926

## Abstract

Project summary
Lung function is essential to sustain life and depends on the continuous neutralization of inhaled pathogens,
particles, and noxious substances. The mucosal epithelial barrier of the lung is the first line of defense against
contaminants. In the case of a compromised mucosal epithelial barrier, epithelial alarmins recruit inflammatory
responses to neutralize threats and aid in the restoration of lung homeostasis. The mechanisms that regulate
inflammation must accommodate sensitivity to pathogens while preventing excessive inflammation that results
in further epithelial damage. That excessive inflammation is a defining feature of major lung diseases like
asthma and COPD underscores the need for regulatory mechanisms that safeguard the lung against excessive
inflammation.
The interaction between receptor C-type lectin-like 2 (Clec-2) and its ligand Podoplanin (Pdpn) has been found
to regulate inflammatory responses in various tissues. We found that both Clec-2-deficiency and Pdpn-
deficiency cause spontaneous lung inflammation and asthma-like disease in mice. Specific blocking of Clec-
2/Pdpn interaction increases the epithelial production of alarmins and the susceptibility to allergic asthma.
Taken together, we hypothesize that Clec-2/Pdpn crosstalk is a mechanism that, when intact, resists
inflammation and promotes lung homeostasis. We propose to exploit single-cell genomics to identify all of the
cell types and subsets that express Clec-2 and Pdpn, and to spatially map them over the lung's anatomy. In so
doing, we will identify putative cellular circuits that mediate Clec-2/Pdpn interactions, and test these circuits
using in vivo mouse genetics. Finally, we propose to investigate the cellular mechanisms that link Clec-2/Pdpn
crosstalk to the regulation of epithelial alarmins and lung inflammation. Overall, we will use Clec-2/Pdpn
interactions as an entry point to exploring the cellular circuits and molecular mechanisms that safeguard lung
homeostasis, with the goal to identify new therapeutic targets for inflammatory diseases.
My ultimate training goal is to become an independent scientist focusing on cellular circuits that support lung
function and that are dysregulated in disease. With the guidance and mentorship of Dr. Aviv Regev at the
Broad Institute and Dr. Vijay Kuchroo at Brigham and Women's Hospital, I composed a training plan that will
provide me the essential technical and pedagogical training to successfully advance my training goals.

## Key facts

- **NIH application ID:** 10069014
- **Project number:** 1F32HL154638-01
- **Recipient organization:** BROAD INSTITUTE, INC.
- **Principal Investigator:** Daniel Thomas Montoro
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $64,926
- **Award type:** 1
- **Project period:** 2020-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10069014

## Citation

> US National Institutes of Health, RePORTER application 10069014, Cellular crosstalk in the maintenance of lung epithelial homeostasis (1F32HL154638-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10069014. Licensed CC0.

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