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Transcriptional Regulation of Endothelial Cells after Neonatal Lung Injury

Award Number: R01HL141174
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2018
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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Transcriptional Regulation of Endothelial Cells after Neonatal Lung Injury - PROJECT SUMMARY. Advances in neonatal critical care have greatly improved the survival of preterm infants but the long-term complications of prematurity, including Bronchopulmonary dysplasia (BPD), cause mortality and morbidity later in life. After premature birth, transition of the lung to a non-aqueous environment appears sufficient to disrupt subsequent alveolar growth and the attendant vascular structures required for effective gas exchange. This is further exacerbated when the preterm lung is exposed to supplemental oxygen and positive pressure ventilation. Irreversible loss of alveolar capillaries and vascular remodeling after oxygen exposure cause pulmonary hypertension (PH) seen in patients with severe BPD (BPD-PH). There is an urgent need for innovative therapeutic approaches to stimulate neonatal lung angiogenesis and preserve respiratory function in BPD-PH infants. My laboratory recently created PEI600-MA5/PEG-OA/Cho nanoparticles that can deliver non-integrating expression plasmids with pro-angiogenic genes into pulmonary microvascular endothelial cells with the purpose of stimulating neonatal lung angiogenesis. We also identified a specialized subpopulation of pulmonary endothelial progenitor cells (EPCs), FOXF1+ EPCs, that are a subset of recently discovered general capillary cells (gCAPs). Transplantation of FOXF1+ gCAPs increased neonatal lung angiogenesis and alveolarization in mice with congenital deficiency of alveolar capillaries. We propose to test the hypothesis that increasing neonatal lung angiogenesis via the nanoparticle FOXF1 gene therapy or the FOXF1+ gCAP cell transplantation will prevent PH and improve lung function in mouse and rat models of BPD- PH. In Aim 1, we will determine whether the nanoparticle FOXF1 gene therapy has a long-term beneficial effect in BPH-PH by preventing PH and right ventricular (RV) hypertrophy, and accelerating lung regeneration after neonatal hyperoxic lung injury. We will also identify novel downstream targets of FOXF1 in regenerating endothelial cells and test whether FOXF1 recruits STAT3 to the chromatin to activate endothelial enhancers. Our studies will determine if the FOXF1-STAT3 protein-protein interactions are required for lung regeneration in BPH-PH models. In Aim 2, we will determine whether transplantation of donor FOXF1+ gCAPs has a long- term beneficial effect by preventing PH and RV hypertrophy in mouse model of BPH-PH. We will also test requirements of the DLL4/NOTCH signaling pathway for the ability of donor FOXF1+ gCAPs to stimulate proliferation and tube formation in recipient endothelial cells during lung regeneration after hyperoxic injury. Finally, we will produce mouse FOXF1+ gCAPs from embryonic stem cells (ESCs) in vitro (via directed differentiation of ESCs into FOXF1+ gCAPs) and in vivo (via interspecies mouse-rat chimeras). Mouse ESC- derived FOXF1+ gCAPs will be used for cell therapy to prevent or delay PH and RV hypertrophy in mouse BPD-PH model. Altogether, the proposed preclinical studies will directly test whether endothelial delivery of the FOXF1 vector or cell therapy with FOXF1+ gCAPs have therapeutic potential in BPD-PH.


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 = $666,314 )
2025	2025	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Lung Diseases Research	001	7	7/18/2025	NON-COMPETING CONTINUATION	$666,314
2025	2021	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Lung Diseases Research	000	4	1/30/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $666,314

Issue Date FY: 2024 ( Subtotal = $643,943 )
2024	2024	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Lung Diseases Research	000	6	7/11/2024	NON-COMPETING CONTINUATION	$643,943
														Subtotal = $643,943

Issue Date FY: 2023 ( Subtotal = $674,083 )
2023	2023	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Lung Diseases Research	000	5	9/15/2023	COMPETING CONTINUATION	$674,083
														Subtotal = $674,083

Issue Date FY: 2021 ( Subtotal = $524,323 )
2021	2021	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Lung Diseases Research	000	4	3/16/2021	NON-COMPETING CONTINUATION	$524,323
														Subtotal = $524,323

Issue Date FY: 2020 ( Subtotal = $524,323 )
2020	2020	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Lung Diseases Research	000	3	3/27/2020	NON-COMPETING CONTINUATION	$524,323
														Subtotal = $524,323

Issue Date FY: 2019 ( Subtotal = $524,323 )
2019	2019	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Lung Diseases Research	000	2	3/25/2019	NON-COMPETING CONTINUATION	$524,323
														Subtotal = $524,323

Issue Date FY: 2018 ( Subtotal = $524,323 )
2018	2018	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Lung Diseases Research	000	1	2/24/2018	NEW	$524,323
														Subtotal = $524,323

Grand Total All Awards = $4,081,632

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Transcriptional Regulation of Endothelial Cells after Neonatal Lung Injury

Award Number: R01HL141174

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2018

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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