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Neutrophils and Monocytes in Pediatric Ischemic Stroke

Award Number: R01NS125788
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2022
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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Neutrophils and Monocytes in Pediatric Ischemic Stroke - PROJECT SUMMARY (Description) Ischemic stroke affects around 1 in 1600 to 4000 births, has the highest incidence in neonates and infants (< one year of age), and may cause neurological sequalae, including motor and cognitive deficits. Infection and immune responses are a major risk factor for pediatric stroke, but no immune-directed therapies are available. In fact, supportive measures remain the mainstay of pediatric stroke care, since the lytic treatment carries a high in neonates with fragile cerebrovascular vessels. In this project, we will use a murine model of pediatric stroke, with and without lipopolysaccharides (LPS)-sensitization, to test the pathological roles of neutrophils and monocytes towards the development of immunomodulation therapies. Aim 1: To clarify how immune cells breach the pial/glia limitans barrier in pediatric LPS/stroke. We will use flow cytometry and single-cell RNA-Seq analysis to determine the compositions and transcriptome of immune cells in the meninges after LPS/stroke, and test whether anti-MMP9 treatment prevents the neutrophil influx. Aim 2: To test whether there are two waves of monocytic infiltrates with distinct functions in pediatric stroke. We will use CCR2-CreER mice to track monocytic infiltrates and single-cell RNA-Seq analysis, as well as, block the influx of monocytes at different stage after stroke to address this issue. Aim 3: To determine what constitutes the meninges-incurred pathogenicity of neutrophils after pediatric LPS/stroke. Our RNA-Seq results suggest that neutrophils acquire IL-36gamma, a novel family of the IL-1 family cytokine, in the meninges. We will validate these findings and test the benefits of anti-IL36R treatment. Successful completion of this project will shed insights into the mechanisms of pediatric ischemic stroke and whether neutrophil/monocyte-targeted immunomodulation therapies could provide better clinical management.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $430,947 )
2025	2025	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	6/20/2025	NON-COMPETING CONTINUATION	$430,947
														Subtotal = $430,947

Issue Date FY: 2024 ( Subtotal = $418,019 )
2024	2024	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	7/24/2024	NON-COMPETING CONTINUATION	$418,019
														Subtotal = $418,019

Issue Date FY: 2023 ( Subtotal = $430,947 )
2023	2023	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	6/20/2023	NON-COMPETING CONTINUATION	$430,947
														Subtotal = $430,947

Issue Date FY: 2022 ( Subtotal = $430,947 )
2022	2022	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	5/26/2022	NEW	$430,947
														Subtotal = $430,947

Grand Total All Awards = $1,710,860

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Neutrophils and Monocytes in Pediatric Ischemic Stroke

Award Number: R01NS125788

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 06/01/2022

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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