# Protective monocytes in cerebral ischemic tolerance

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2021 · $370,781

## Abstract

Project Summary/Abstract
Stroke is a prevalent and devastating disease with limited therapeutic options. Inflammation and
immune cells are major components in the pathophysiology of ischemic stroke and contribute to acute
and delayed tissue injury. However, our incomplete understanding of the factors regulating the immune
responses triggered by cerebral ischemia remains a significant obstacle to the development of effective
therapeutic interventions based on modulating post-ischemic inflammation. Besides activation of brain
resident immune cells, ischemic stroke is characterized by the recruitment of peripheral innate and
adaptive immune cells that participate in the inflammatory response and contribute to the damage.
Monocyte-derived macrophages (MMØ) are a major component of the cellular innate immune response
to ischemic stroke. MMØ infiltrate the ischemic lesion and perilesional territories early after ischemia
and reside in the injured territory for prolonged periods of time. These observations raise the possibility
that MMØ contribute to the entire inflammatory process from initiation to resolution with the potential of
modulating the outcome of cerebral ischemic injury. The long-term goal of this research program is to
elucidate the role of MMØ in stroke pathophysiology and develop the experimental framework for new
preventative and therapeutic approaches for ischemic stroke. In the present application, we will test the
hypothesis that MMØ are present in the ischemic territory as functionally divergent and molecularly
definable populations and that tissue hypoxia is an important determinator for MMØ differentiation and
revelation of their neuroprotective capacity. This hypothesis, supported by relevant preliminary results,
will be tested by determining: (a) the transition of MMØ from monocytes to long-term resident immune
cells in the post-ischemic brain (Aim 1), (b) the effects of the hypoxic environment on tissue distribution
and polarization of MMØ (Aim 2), and (c) the role of hypoxia-inducible factor 1α (HIF1α) and glycolytic
metabolism in the functional polarization of brain-infiltrating MMØ and their effects on stroke outcome
(Aim 3). These goals will be achieved using a mouse model of transient focal cerebral ischemia with
assessment of histological and neurological outcome together with a novel model for classifying brain
MMØ. This proposal may open the way to new avenues for stroke prevention and therapy based on
modulation of MMØ and their precursor, the peripheral blood monocyte.

## Key facts

- **NIH application ID:** 10220141
- **Project number:** 5R01NS081179-09
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Josef Anrather
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $370,781
- **Award type:** 5
- **Project period:** 2012-09-15 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10220141

## Citation

> US National Institutes of Health, RePORTER application 10220141, Protective monocytes in cerebral ischemic tolerance (5R01NS081179-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10220141. Licensed CC0.

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