# Reconstructing Cell-Cell Interactions in Diverse Inflammatory Environments

> **NIH NIH R35** · UNIVERSITY OF COLORADO · 2022 · $363,627

## Abstract

SUMMARY
Neutrophils, the most abundant innate immune cell type, play a critical role in clearing infections, healing wounds,
and repairing damaged tissues. Our laboratory seeks to understand how diverse inflammatory signals regulate
the neutrophil response to inflammation using engineered in vitro platforms designed to mimic in vivo biology
with human cells. Specifically, we are interested in determining how (i) secreted inflammatory signals, (ii)
multicellular interactions, and (iii) the extracellular matrix regulate neutrophil behavior with the long-term goal of
identifying targets to modulate neutrophil recruitment and function to treat infections and neutrophil-associated
diseases. To properly function, neutrophils must integrate the unique set of cues released by each inflammatory
environment into a specific, directed, and tightly regulated response. Defective neutrophil recruitment, excessive
neutrophil infiltration, or improperly controlled neutrophil function contributes to chronic infections, tissue
damage, and the progression of diseases including cancer, cardiovascular disease, autoimmune disease, and
fibrosis. The individual steps of the neutrophil response (activation, extravasation, migration, and antimicrobial
function) are coordinated by a wide variety of secreted proinflammatory signals released by the activated
vasculature, tissue resident cells, circulating cells, and pathogens; however, the different mechanisms through
which each of these soluble signals and cell populations regulate neutrophil recruitment and function are
undefined. Importantly, how neutrophil behavior varies in response to differing inflammatory cues and how
neutrophils integrate multiple cues into a directed response remain unanswered questions. This knowledge gap
exists due to the limitations of the current experimental platforms, which fail to capture the complex milieu of
signals, multicellular interactions, or three-dimensional architecture of the in vivo environment. To address this
challenge, we have recently developed a novel inflammation-on-a-chip device that includes key aspects of the
inflammatory environment including a model blood vessel, primary human immune cells, extracellular matrix,
and a source of live pathogen or proinflammatory cytokine to investigate the primary human neutrophil response
in a physiologically relevant in vitro model. Over the next five years, we will exploit the modularity of our
inflammation-on-a-chip device to develop a comprehensive understanding of how individual inflammatory stimuli
(pathogens, pathogen-associated molecular patterns, damage-associated molecular patterns, cytokines) and
interactions with varied inflammatory cell populations (endothelial cells, pericytes, macrophages, platelets)
regulate neutrophil function. We will identify key signaling molecules and signaling network hubs that broadly
regulate the neutrophil response or are uniquely important for the neutrophil response to individual stimuli. This
...

## Key facts

- **NIH application ID:** 10497648
- **Project number:** 1R35GM146737-01
- **Recipient organization:** UNIVERSITY OF COLORADO
- **Principal Investigator:** Laurel Erin Hind
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $363,627
- **Award type:** 1
- **Project period:** 2022-08-01 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10497648

## Citation

> US National Institutes of Health, RePORTER application 10497648, Reconstructing Cell-Cell Interactions in Diverse Inflammatory Environments (1R35GM146737-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10497648. Licensed CC0.

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