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Ependymal Dysfunction in Neonatal Post-Hemorrhagic Hydrocephalus

Award Number: R01NS110793
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: 04/15/2019
PERIOD OF PERFORMANCE END DATE: 01/31/2025

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Ependymal Dysfunction in Neonatal Post-Hemorrhagic Hydrocephalus - Project Summary Germinal matrix hemorrhage-intraventricular hemorrhage (GMH-IVH) is a significant cause of morbidity and mortality in preterm infants, with 14,000 new cases each year in the United States. Forty percent of severe GMH- IVH infants have poor outcomes and 25% require long-term treatment for post-hemorrhagic hydrocephalus (PHH), the most common cause of hydrocephalus in North America. Although the link between IVH and PHH is well established, the underlying pathophysiology of PHH is incompletely understood and there are no preventative treatments. Blood breakdown products, iron and hemoglobin, released in the ventricle after IVH result in injury to the cilia-lined ependyma and cause hydrocephalus. While treatment with iron chelation reduces hydrocephalus after IVH, it is unknown how iron and hemoglobin result in ventricular enlargement and ependymal injury. Expression of the hemoglobin-haptoglobin receptor, CD163, is increased after IVH in the ventricular ependyma and may represent an important route of cellular iron uptake leading to injury. We have also demonstrated that the only known cellular iron exporter, ferroportin 1 (FP1), is expressed on ependymal cells and subsequently upregulated in response to IVH. The ependyma is lined by motile cilia, which are implicated in cerebrospinal fluid flow, and primary cilia, which regulate and direct neural precursor cells at the ventricular surface. Genetic models of both motile and primary cilia dysfunction demonstrate abnormal cerebrospinal fluid (CSF) flow and hydrocephalus; however, cilia function has not been evaluated in PHH. We have demonstrated iron-induced cilia injury and dysfunction after IVH. The objective of this proposal is to determine the relationship between iron-induced ependymal injury, cilia dysfunction and hydrocephalus. We will test the central hypothesis that iron transport through CD163 and inhibition of iron export through FP1 at the ventricular surface results in ependymal, subventricular zone (SVZ) and cilia injury, leading to defects in ependymal development and regional CSF flow, culminating in hydrocephalus. We will test our hypothesis in the following Specific Aims: 1) Determine whether CD163 mediates iron-induced ependymal and SVZ injury and hydrocephalus after GMH-IVH. 2) Determine the role of FP1 in iron-mediated ependymal and SVZ injury and hydrocephalus after grade III and grade IV GMH-IVH. 3) Determine the role of iron chelation in CSF outflow after GMH-IVH and identify how cilia dysfunction contributes to iron-mediated ependymal cell injury, CSF flow and hydrocephalus by inactivating postnatal ependymal cilia movement. If successful, these experiments will provide novel targets for prevention of PHH and provide new insight into how cilia dysfunction contributes to hydrocephalus.


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 = $0 )
2025	2023	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	6/4/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $471,733 )
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	4/5/2023	NON-COMPETING CONTINUATION	$471,733
														Subtotal = $471,733

Issue Date FY: 2022 ( Subtotal = $513,499 )
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	1/19/2022	NON-COMPETING CONTINUATION	$462,149
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	4/1/2022	NON-COMPETING CONTINUATION	$51,350
														Subtotal = $513,499

Issue Date FY: 2021 ( Subtotal = $511,015 )
2021	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	2/6/2021	NON-COMPETING CONTINUATION	$511,015
														Subtotal = $511,015

Issue Date FY: 2020 ( Subtotal = $488,431 )
2020	2020	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	1/31/2020	NON-COMPETING CONTINUATION	$488,431
														Subtotal = $488,431

Issue Date FY: 2019 ( Subtotal = $467,502 )
2019	2019	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	4/5/2019	NEW	$467,502
														Subtotal = $467,502

Grand Total All Awards = $2,452,180

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Ependymal Dysfunction in Neonatal Post-Hemorrhagic Hydrocephalus

Award Number: R01NS110793

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: 04/15/2019

PERIOD OF PERFORMANCE END DATE: 01/31/2025

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