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Pathogenic Mechanisms of Inflammatory Subventricular Zone Injury in Preterm Infants

Award Number: R01NS140419
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: 03/13/2025
PERIOD OF PERFORMANCE END DATE: 01/31/2030

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Pathogenic Mechanisms of Inflammatory Subventricular Zone Injury in Preterm Infants - ABSTRACT: Preterm birth is the leading cause of life-long neurodevelopmental impairment (NDI) in infants. Common complications of prematurity such as intestinal perforation confer a significant risk for diffuse myelination deficits and NDI. Diffuse hypomyelination can reliably detected after affected infants reach term corrected ages however, this is often months after the intestinal perforation has occurred. Using our mouse neonatal modeled intestinal perforation (MIP) model, we discovered a previously unrecognized injury to the multiciliated ependymal cell layer that forms the ventricular border of the subventricular zone (SVZ) neural stem cell niche. The functional role the multiciliated ependyma extends beyond controlling CSF flow and barrier formation but is known to involve the regulation of SVZ progenitor populations within the niche. In our MIP model, disruption of the ependyma was associated with increased echogenicity on cranial ultrasound. Our animal research led us to interrogate the SVZ and germinal matrix of preterm infants using cranial ultrasound following intestinal perforation leading to the novel discovery that a subset (~40%) of preterm infants develop subventricular zone echogenicity (SVE) as early as 48 hours after intestinal perforation. Importantly, the development of SVE was a predictor of NDI on the 2- year Bayley test suggesting that SVZ injury is an early mechanism of brain injury and NDI in human preterm infants. Our preliminary data comprising of both single cell and spatial transcriptomic approaches, support the hypothesis that NFkB-enriched IL-1b producing peripheral monocytes traffic onto the ependymal surface of the lateral ventricles via the choroid plexus where they seed the surface of the SVZ. Our preliminary data identified a unique role for IL-1b at disrupting ependymal cell survival relative to TNFa or IL-6. Our preliminary data also revealed that the LXR agonist, 20-aHydroxychoelsterol, suppresses NFkB signaling and IL-1b production in the monocyte/macrophage lineage and appears to prevent MIP-induced SVZ injury. Our central hypothesis is that blood-born monocytes infiltrate the SVZ and increase localized IL-1b production leading to the disruption of the ependymal barrier and collapse of this critical stem cell niche’s functions. Aim 1 will use scavenged blood samples from preterm infants with intestinal perforation to define immune signatures associated with the development of SVE using a scRNAseq approach. Aim 2 will define immune signatures that are associated with murine SVE and compare our findings to the human data generated in Aim 1. We will also investigate the role of monocyte/macrophage accumulation in the choroid plexus and their role in SVZ injury. Aim 3 will utilize genetic approaches to interrogate the specific role of monocytic-derived IL-1b on SVZ injury and determine if 20HC is a viable therapeutic approach to brain injury in preterm infants.


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: 2026 ( Subtotal = $630,892 )
2026	2026	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	3/5/2026	NON-COMPETING CONTINUATION	$63,089
2026	2026	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	2/5/2026	NON-COMPETING CONTINUATION	$567,803
														Subtotal = $630,892

Issue Date FY: 2025 ( Subtotal = $635,386 )
2025	2025	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	3/13/2025	NEW	$635,386
														Subtotal = $635,386

Grand Total All Awards = $1,266,278

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Pathogenic Mechanisms of Inflammatory Subventricular Zone Injury in Preterm Infants

Award Number: R01NS140419

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: 03/13/2025

PERIOD OF PERFORMANCE END DATE: 01/31/2030

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