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Reversing Inflammatory Macrophage Activation as Treatment for Neonatal Intraventricular Hemorrhage and Hydrocephalus

Award Number: K08NS112580
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

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Neonatal Intraventricular hemorrhage (IVH) originates from the underdeveloped germinal matrix, a site of cell rapid cell division adjacent to the lateral ventricles of the brain. IVH leads to post-hemorrhagic hydrocephalus (PHH). Within the same time frame that neonatal IVH occurs, the neonatal brain is also rapidly producing the cells needed for myelination. Oligodendrocytes, the myelin-forming cells of the brain, are derived from oligodendrocyte progenitor cells (OPCs). OPCs are fragile cells - exquisitely sensitive to many factors that are present across multiple neurological diseases such as excitotoxicity, inflammatory cytokines, and oxidative stress. Across a wide spectrum of neurological diseases, neuroinflammation causes OPC loss and failure of myelination. Infiltrating brain macrophages are implicated in many forms of neonatal brain injury. Macrophages are activated by many different stimuli in CNS injury and disease, including blood products released into the ventricular space. Understanding the role of macrophages after IVH is critical to improving outcomes, as macrophage activation mediates white matter injury in other forms of neonatal brain injury. Azithromycin is a commonly prescribed antibiotic that is safe in neonates. Besides its antibiotic properties, azithromycin is also anti-inflammatory and shifts macrophage activation into an anti-inflammatory phenotype that actually promotes tissue recovery rather than injury. Azithromycin has been used in a variety of anti-inflammatory applications including preclinical work in spinal cord injury where it improves tissue sparing and neurological function. Importantly, azithromycin has already undergone rigorous clinical trials in neonates for inflammation-induced lung injury. This study will pharmacologically block infiltrating macrophages in IVH/PHH and test azithromycin’s ability to protect OPCs from macrophage-induced injury in a rat model of neonatal IVH. I will use a combination of in vivo and in vitro experiments to examine macrophage activation, OPC death and myelination with and without azithromycin treatment. My in vivo work will allow us to use neurobehavioral outcomes to assess the efficacy of azithromycin while my in vitro model will allow for in-depth mechanistic studies of macrophage-OPC interaction. This project will support Dr. Miller’s training in studies of neuroinflammation and neurotherapeutics. If successful, this project will pave the way for clinical studies of azithromycin for improving neurological outcome after neonatal IVH.


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: 2024 ( Subtotal = $174,880 )
2024	2024	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	12/8/2023	NON-COMPETING CONTINUATION	$174,880
														Subtotal = $174,880

Issue Date FY: 2023 ( Subtotal = $174,880 )
2023	2023	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	12/13/2022	NON-COMPETING CONTINUATION	$174,880
														Subtotal = $174,880

Issue Date FY: 2022 ( Subtotal = -$10,557 )
2022	2021	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	2/28/2022	NON-COMPETING CONTINUATION	-$185,437
2022	2021	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	3	6/21/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$14,266
2022	2021	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	3/1/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$174,880
2022	2020	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	1	6/21/2022	NEW	-$14,266
														Subtotal = -$10,557

Issue Date FY: 2021 ( Subtotal = $185,437 )
2021	2021	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	6/24/2021	NON-COMPETING CONTINUATION	$185,437
														Subtotal = $185,437

Issue Date FY: 2020 ( Subtotal = $185,437 )
2020	2020	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	6/19/2020	NEW	$185,437
														Subtotal = $185,437

Grand Total All Awards = $710,077

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Reversing Inflammatory Macrophage Activation as Treatment for Neonatal Intraventricular Hemorrhage and Hydrocephalus

Award Number: K08NS112580

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

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