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The Role of Lung Megakaryocytes in Airway Disease after Neonatal Hyperoxia

Award Number: K08HL155491
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 04/01/2022
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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The Role of Lung Megakaryocytes in Airway Disease after Neonatal Hyperoxia - Former preterm infants are exposed to oxygen (O2) after birth which results in long-term developmental impacts on the lung. Approximately 70% of infants born extremely prematurely (<29 weeks’ gestational age) will have increased pulmonary morbidity and/or early childhood wheezing disorders even though many are not diagnosed with Bronchopulmonary Dysplasia (BPD). These infants are especially vulnerable to airway hyperreactivity (AHR) after respiratory viral infections through poorly understood mechanisms. Herein, we utilize a low-dose hyperoxia mouse model and a unique pediatric human tissue repository grounded on a new discovery that neonatal O2 increases the abundance of lung megakaryocytes (MKs), an understudied myeloid cell biased toward immunomodulatory functions. After respiratory viral infection, lung MKs release profibrotic cytokines such as Thrombospondin-1 (TSP-1), a critical inflammatory regulator and activator of transforming growth factor beta 1 (TGFβ1) that drives fibrosis. We hypothesize that neonatal hyperoxia primes the lung for AHR by increasing the recruitment of lung MKs and predisposing MKs to release pro-fibrotic factors (e.g. TSP-1) after infection. Aim 1 will determine how the hyperoxic lung environment after birth effects lung MK recruitment and seeding including how O2 at different developmental ages and MK depletion affect the lung MK population. Aim 2 will determine how neonatal hyperoxia effects lung MK transcriptome before and after activation using in vitro cytokine assays and RNAseq. Experiments will also determine if AHR is MK or TSP-1 dependent by comparing Influenza infection models of MK-depleted mice to transgenic mice with the TSP-1 gene deleted from MKs. Aim 3 will determine how neonatal O2 effects the bone marrow MK pool, including its effects on platelet production. This proposal is a five-year mentored research award and training plan for Dr. Andrew Dylag, MD to investigate oxygen-induced mechanisms of airway dysfunction in both mice and procured human tissues. Dr. Dylag is an Assistant Professor of Pediatrics (Neonatology) at the University of Rochester Medical Center. The research herein builds on Dr. Dylag’s experience as a clinical neonatologist and a basic scientist interested in O2 injury and post-hyperoxia airway hyperreactivity (AHR). As part of his career development plan, Dr. Dylag will attain expertise through four (4) career aims: 1) Increase knowledge and technical skills in the investigation of lung development and repair after injury using translational in vivo models, 2) Targeted training in bioinformatics analysis including transcriptomics, 3) Develop expertise in applying in vivo laboratory discoveries to human tissues and clinical human disease, and 4) Develop the necessary skills to lead an effective translational research program. Dr. Dylag will attain his stated goals by applying new skills in flow cytometry, immunohistochemistry, transcriptomics, and targeted bioinformatics training to a mouse and human tissues. At the completion of this career development award, Dr. Dylag will have interrogated one mechanistic role of how early life O2 drives AHR, advancing our understanding of how neonatal O2 exposures drive longer-term pulmonary morbidity.


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 = $162,141 )
2026	2026	UNIVERSITY OF ROCHESTER	910 GENESEE ST	ROCHESTER	NY	14611	MONROE	USA	Lung Diseases Research	000	5	4/28/2026	NON-COMPETING CONTINUATION	$162,141
														Subtotal = $162,141

Issue Date FY: 2025 ( Subtotal = $162,141 )
2025	2025	UNIVERSITY OF ROCHESTER	910 GENESEE ST	ROCHESTER	NY	14611	MONROE	USA	Lung Diseases Research	000	4	2/22/2025	NON-COMPETING CONTINUATION	$162,141
														Subtotal = $162,141

Issue Date FY: 2024 ( Subtotal = $162,141 )
2024	2024	UNIVERSITY OF ROCHESTER	910 GENESEE ST	ROCHESTER	NY	14611	MONROE	USA	Lung Diseases Research	000	3	3/8/2024	NON-COMPETING CONTINUATION	$162,141
														Subtotal = $162,141

Issue Date FY: 2023 ( Subtotal = $162,141 )
2023	2023	UNIVERSITY OF ROCHESTER	500 JOSEPH C WILSON BLVD	ROCHESTER	NY	14627	MONROE	USA	Lung Diseases Research	000	2	2/27/2023	NON-COMPETING CONTINUATION	$162,141
														Subtotal = $162,141

Issue Date FY: 2022 ( Subtotal = $162,141 )
2022	2022	UNIVERSITY OF ROCHESTER	500 JOSEPH C WILSON BLVD	ROCHESTER	NY	14627	MONROE	USA	Lung Diseases Research	000	1	3/25/2022	NEW	$162,141
														Subtotal = $162,141

Grand Total All Awards = $810,705

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The Role of Lung Megakaryocytes in Airway Disease after Neonatal Hyperoxia

Award Number: K08HL155491

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 04/01/2022

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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