# Integrative Genomics of Acute Asthma Control

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2021 · $822,505

## Abstract

The overarching hypothesis underpinning our research is that inter-individual differences in asthma control
result from the interplay of genetic and environmental factors organized in discrete molecular networks. During
the first grant cycle, we explored this hypothesis by defining the molecular determinants of asthma control in
well characterized patient populations using integrative genomic approaches. Among our most notable
observations was our discovery that asthmatics with suboptimal asthma control demonstrate a peripheral blood
gene expression signature indicative of activation of the TREM1 signaling pathway. Triggering Receptor
Expressed On Myeloid Cells 1 (TREM1) is a cell-surface receptor expressed on monocytes and macrophages
that plays a critical role in modulating both the innate and adaptive immune response. We now hypothesize
that the activation of TREM1 is a critical early molecular event in the worsening of asthma control, and that
inhibition of this signaling pathway represents new and effective non-steroidal strategy for maintaining long-
term asthma control. We will test these hypotheses in the following complementary Specific Aims: In Specific
Aim 1 we will use both single cell and bulk RNA-sequencing to characterize the patterns of TREM1 expression
and pathway activation in monocyte subtypes from 100 children and young adults with variable asthma control.
Our goals are to define and classify monocyte subsets based on their TREM1 activation status; correlate
monocyte-specific TREM1 activation signatures with asthma control; and assess whether these signatures can
predict deterioration in asthma control and exacerbation. In Specific Aim 2 we will evaluate soluble TREM1
(sTREM1) as a potential biomarker of asthma control. sTREM1 is shed from cell surfaces and plasma sTREM1
levels correlate with clinical severity in several inflammatory conditions. We will measure sTREM1 plasma
levels in samples from more than 2,500 asthmatics to determine (i) if sTREM1 can serve as a biomarker of
asthma control and predict asthma exacerbation; (ii) if high sTREM1 levels define a specific clinical asthma
subtype or responsiveness to specific asthma therapies; and (iii) if sTREM1 levels are determined by specific
genetic or environmental exposures, and, if so, do they mediate correlations with asthma control? In Specific
Aim 3, we will use an established mouse model of allergic airway inflammation to evaluate the therapeutic
potential of inhibition of the TREM1 signaling pathway in the treatment of asthma. We anticipate that LR12 will
demonstrate strong efficacy in these models, providing essential pre-clinical data to support future first-in-
human trials of this compound in asthmatic patients.

## Key facts

- **NIH application ID:** 10122586
- **Project number:** 2R01HL118455-05
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Joshua Millstein
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $822,505
- **Award type:** 2
- **Project period:** 2014-08-06 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10122586

## Citation

> US National Institutes of Health, RePORTER application 10122586, Integrative Genomics of Acute Asthma Control (2R01HL118455-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10122586. Licensed CC0.

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