# Imaging macrophage and microglial functional diversity in stroke

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2021 · $399,783

## Abstract

Treatment of stroke is limited to only a few approved therapeutic options that have to be administered within
rigid short timeframes resulting in the exclusion of many patients. The overarching goal of this proposal is to
further our understanding of different microglia (Mg) and macrophage (MØ) phenotypes to drive the
development of new personalized therapies for stroke. Activated Mg and MØ are the dominant inflammatory
cells in stroke, peaking early and persisting into the chronic stage. These cells are highly dynamic and
modulate both damage and repair. Human stroke trials using broad nonspecific anti-inflammatory therapies
have failed, likely in part because human stroke is heterogeneous and reparative cells may have been
inadvertently blocked in many patients. However, current knowledge on these cells and their functions had
been derived mostly from in vitro assays that prevent longitudinal tracking in living animals and patients. How
different Mg/MØ subtypes function in vivo, especially in response to interventions, is poorly understood. To
enable in vivo investigations of Mg and MØ functions, we propose to thoroughly define the transcriptomes and
proteomes and of Mg and MØ subsets in stroke to identify potential imaging targets for damaging and
reparative Mg/MØ phenotypes. Oxidative stress and phagocytosis are two key functional manifestations of Mg/
MØ activity that can be manipulated for stroke therapy, and can be used to functionally differentiate between
damaging and reparative Mg/MØ. Mg/MØ-derived reactive oxygen species (ROS) increase damage after
stroke, and are mostly produced by M1-type cells. Phagocytosis is important in repair, but can be seen in both
M1- and M2-type Mg/MØ. Our previous transcriptome profiling identified myeloperoxidase (MPO) as a major
product secreted by M1-type cells. MPO plays key roles in increasing oxidative stress and tissue damage after
stroke, and remains elevated in the ischemic brain for weeks. Moreover, MPO can modulate the inflammatory
response toward damage by interacting with the mannose receptor, though a key role of the mannose receptor
is repair. Interestingly, mannose receptors are abundantly expressed on M2-type Mg and MØ, and can be
increased by D-mannose administration even in M1-type cells. However, how D-mannose treatment will
change Mg and MØ phenotypes in vivo in stroke is unknown. The proposed experiments will deepen our
fundamental understanding of the functional diversity and plasticity of Mg and MØ in stroke, identify Mg/MØ
based on their functional phenotypes, and lead to new imaging targets urgently needed for stroke. The specific
aims are 1A) perform transcriptome-proteomics analysis to profile damaging and reparative Mg and MØ
phenotypes and discover potential targets for these phenotypes, 1B) validate imaging agents to report on the
phenotypes of Mg and MØ in stroke, 3) perform in vivo imaging to map damaging and reparative Mg and MØ
activity after stroke, and 4) investigate cha...

## Key facts

- **NIH application ID:** 10124445
- **Project number:** 5R01NS103998-04
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** John W Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $399,783
- **Award type:** 5
- **Project period:** 2018-05-15 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10124445

## Citation

> US National Institutes of Health, RePORTER application 10124445, Imaging macrophage and microglial functional diversity in stroke (5R01NS103998-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10124445. Licensed CC0.

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