# Mechanisms of non-IgE Mast Cell Activation by Environmental Particulates

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2020 · $515,084

## Abstract

PROJECT SUMMARY
Inflammation is recognized as a major underlying mechanism for a number of diseases with an environmental
etiology that have serious pathologic outcomes such as autoimmunity, cancer, cardiovascular disease, lung
disease, neurodegeneration as examples. Mast cells represent a major sensory arm of the body's innate
immune system by functioning as environmental `sensors' to communicate with other physiological and/or
immune responses due to their widespread tissue presence at mucosal surfaces, near blood vessels and the
nervous system. Through funding from R01 ES019311, we have begun to unravel novel mechanisms of non-
IgE mast cell activation that contribute to inflammation. While mast cells are implicated as pathogenic in a
number of diseases beyond allergy little is known on mechanisms and even less is known regarding how
environmental toxicants trigger mast cell responses that contribute to these disease outcomes. Therefore, our
overarching research goal has been focused on delineating the role of mast cells in environmental health
through better understanding of their role as first responders in environmental insult, resulting effects on innate
and adaptive immunity, and their communication with other cells and physiological systems. Our research has
uncovered novel non-IgE mediated mechanisms of mast cell activation driven by particulates (e.g.
nanoparticles, air pollution particulate matter, silica, etc) that contributes to adverse outcomes in the pulmonary
and cardiovascular system. In addition, through genome wide association studies using the hybrid mouse
diversity panel as well as transcriptomics studies we have uncovered novel genetic regulation of non-IgE mast
cell activation driven by particulates. In particular, we have found a regulatory role for thioredoxin interacting
protein (Txnip) in non-IgE mast cell activation. In this proposal, we will investigate both redox-independent and
-dependent Txnip regulation of mast cell activation by environmental particulates (nanoparticles and ambient
particulate matter) and its influence on G protein-coupled receptors, glycolysis, redox regulation and granule
exocytosis. In addition, we will investigate the role of Txnip using mast cells from patients with chronic
idiopathic urticaria (a mast cell activation disorder largely driven by non-IgE mechanisms and which is thought
to be triggered by environmental exposures). Our overall goal is to delineate the role mast cells in
environmental health through better understanding of their role as first responders in environmental insult, their
activation by particulates and novel mechanisms of non-IgE activation that contributes to disease outcomes.

## Key facts

- **NIH application ID:** 9970127
- **Project number:** 2R01ES019311-12
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Jared Michael Brown
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $515,084
- **Award type:** 2
- **Project period:** 2010-08-10 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9970127

## Citation

> US National Institutes of Health, RePORTER application 9970127, Mechanisms of non-IgE Mast Cell Activation by Environmental Particulates (2R01ES019311-12). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9970127. Licensed CC0.

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