# Neonatal Stroke: The Role of Microglia-derived Extracellular Vesicles

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $491,614

## Abstract

Abstract
Neonatal (perinatal) arterial ischemic stroke is as common as in the elderly and is a major cause of
long-term neurological and cognitive deficits, including cerebral palsy and neurodevelopmental
disabilities. Literature has emerged that the stage of brain development at the time of stroke has a
major impact on the pathophysiological mechanisms of brain damage, but there are no effective
treatments. Inflammation is a hallmark of perinatal brain injury and affects both early injury and brain
repair and connectivity later in life. We discovered that microglia serve as endogenous protectants after
acute stroke in neonatal rats and mice, including protection by removing apoptotic neuronal debris,
limiting neuroinflammation and protecting blood-brain barrier integrity. We will determine whether
microglial cells exert neuro- and vasoprotective effects via release of extracellular vesicles (EV). The
fast-growing EV field as the fundamental way of cell-cell communication without direct cell-cell contacts
in healthy and diseased organism has demonstrated heterogeneity of EV depending on the cell type
releasing them, the mechanism of release and a neurodegenerative scenario.
We hypothesize that microglial cells alleviate injury after neonatal stroke in part via released microglia-
derived EV (MEV). In three aims, we will determine how neonatal stroke changes MEV properties and
their communication with cells in brain slices and microglial cells that isolated after acute stroke (Aim 1);
examine effects of disrupted lipid CD36-dependent signalling and disrupted EV release in the brain on
neuroinflammation and injury in two mouse models—neonatal stroke or intracerebral IL1beta injection.
We will analyse in vivo effects of halted EV release on neuronal and microglial transcriptome/proteome
profiles in same injured neonatal brain (Aim 2); and determine if MEV administration early after
neonatal stroke protects short-term and enhance long-term brain repair (Aim 3).
To understand the mechanistic role of MEV and their therapeutic potential for neonatal stroke, we will
utilize state-of-the art experimental tools, including a clinically relevant perinatal focal arterial stroke
model that we invented, in conjunction with loss-of-function and gain-of function genetic and
pharmacological approaches and advanced non-invasive imaging methodologies. We will manipulate
EV release from neurons (CRISP editing approach), isolate and characterize individual EV and MEV
fractions (super-sensitive ImageStreamX technology and MEV “cargo”), image MEV communication
with resting/activated microglia and the vasculature (live imaging), and utilize novel double transgenic
RiboTag mice to examine in vivo real time microglia-neuron molecular crosstalk. The proposed studies
will enhance the understanding of cell signalling and communication and help achieve our long-term
goal to identify novel therapeutic targets to create effective and safe therapy for neonatal stroke.

## Key facts

- **NIH application ID:** 10201749
- **Project number:** 5R01NS044025-17
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Zinaida S Vexler
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $491,614
- **Award type:** 5
- **Project period:** 2002-09-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10201749

## Citation

> US National Institutes of Health, RePORTER application 10201749, Neonatal Stroke: The Role of Microglia-derived Extracellular Vesicles (5R01NS044025-17). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10201749. Licensed CC0.

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