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DLL4 in the Developing Lung and Bronchopulmonary Dysplasia (BPD)

Award Number: R01HL162937
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2023
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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DLL4 in the Developing Lung and Bronchopulmonary Dysplasia (BPD) - Bronchopulmonary dysplasia is a debilitating lung disease in premature infants characterized by disrupted lung vascularization and alveolarization. The endothelial cell (EC) molecular players that regulate normal and abnormal (BPD) alveolarization remain unclear. Our data in Dll4+/- mice indicate that Delta-like protein 4 (DLL4), an EC notch ligand, is required for lung vascularization and alveolarization. Specifically, DLL4 appears to regulate the development of Car4+EC, a lung-specific EC subset that interacts with alveolar epithelial type I cells (AT1). Interestingly, we also found that the AT1 population is depleted in Dll4+/- mice, as well as mice with EC- specific Dll4 deletion [Dll4EC+/-] in relation with impaired EC hepatocyte growth factor - AT1 MET [HGF receptor] signaling. Examining DLL4’s role in BPD, we noted that both in experimental BPD and in human BPD, there was decreased DLL4 expression and deviant lung vascularization. Testing a new therapy for BPD, we noted that ciclesonide (CIC), a synthetic glucocorticoid pro-drug with brain-sparing effects, rescued hyperoxia (HOX)- induced DLL4 repression in the mouse lung and in human pulmonary microvascular endothelial cells (HPMEC). These data inform our hypothesis that EC-DLL4 regulates CAR4+ EC and AT1 development during distal lung morphogenesis, and disruption of EC-DLL4 signaling in hyperoxia programs vascular and alveolar defects in BPD. We will investigate this hypothesis by: 1) Testing whether EC-DLL4 regulation of CAR4+ EC is critical for lung vascularization, 2) Defining the molecular pathways by which EC-DLL4 regulates AT1 development during lung ontogeny, and 3) Determining whether repression of EC DLL4 signaling programs experimental and human BPD. In Aim 1, we will study how EC-Dll4 deletion in sequential lung stages reprograms lung EC fate, heterogeneity and the Car4+ EC population. Cell autonomous regulation of CAR4+ fate and angiogenesis by DLL4 will be probed in primary and Dll4-deficient HPMEC lines we created. In Aim 2, we will study regulation of AT1 development/function and alveolarization by EC DLL4. We will use single cell RNA sequencing to identify the EC ligand - AT1 receptor interactions and AT1 molecular pathways disrupted with EC Dll4 deletion. We will also study whether Dll4 loss disrupts EC angiocrine signaling through hepatocyte growth factor. In Aim 3, we will combine molecular phenotyping of human BPD samples with studies in Dll4EC -/- vs. +/- vs. +/+ mice to determine EC- Dll4’s role in disrupting EC fate, AT1 ontogeny and lung morphogenesis in HOX. The therapeutic mechanisms by which ciclesonide rescues DLL4 signaling and lung injury in HOX will also be tested. Our proposal impacts the field by discovering DLL4’s role in lung EC fate specification and AT1 ontogeny using innovative strategies. The significance lies in addressing critical barriers underpinning the vascular origins of BPD and translational potential. In SA1 and SA2, we examine DLL4-regulation of Car4 EC and AT1 ontogeny as critical mechanisms underpinning DLL4-regulation of lung development. In SA3, we study DLL4’s role in BPD, and test the efficacy of ciclesonide to rescue DLL4 signaling and mitigate BPD in a pre-clinical model.


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 = $550,907 )
2026	2026	CHILDRENS MERCY HOSPITAL	2401 GILLHAM RD	KANSAS CITY	MO	64108	JACKSON	USA	Lung Diseases Research	001	4	3/25/2026	NON-COMPETING CONTINUATION	$16,863
2026	2026	CHILDRENS MERCY HOSPITAL	2401 GILLHAM RD	KANSAS CITY	MO	64108	JACKSON	USA	Lung Diseases Research	000	4	3/6/2026	NON-COMPETING CONTINUATION	$534,044
														Subtotal = $550,907

Issue Date FY: 2025 ( Subtotal = $566,447 )
2025	2025	CHILDRENS MERCY HOSPITAL	2401 GILLHAM RD	KANSAS CITY	MO	64108	JACKSON	USA	Lung Diseases Research	000	3	3/25/2025	NON-COMPETING CONTINUATION	$509,803
2025	2025	CHILDRENS MERCY HOSPITAL	2401 GILLHAM RD	KANSAS CITY	MO	64108	JACKSON	USA	Lung Diseases Research	001	3	7/29/2025	NON-COMPETING CONTINUATION	$56,644
														Subtotal = $566,447

Issue Date FY: 2024 ( Subtotal = $561,247 )
2024	2024	CHILDRENS MERCY HOSPITAL	2401 GILLHAM RD	KANSAS CITY	MO	64108	JACKSON	USA	Lung Diseases Research	000	2	1/29/2024	NON-COMPETING CONTINUATION	$515,432
2024	2024	CHILDRENS MERCY HOSPITAL	2401 GILLHAM RD	KANSAS CITY	MO	64108	JACKSON	USA	Lung Diseases Research	001	2	6/14/2024	NON-COMPETING CONTINUATION	$45,815
														Subtotal = $561,247

Issue Date FY: 2023 ( Subtotal = $592,536 )
2023	2023	CHILDREN'S MERCY HOSPITAL, THE	2401 GILLHAM RD	KANSAS CITY	MO	64108	JACKSON	USA	Lung Diseases Research	000	1	1/16/2023	NEW	$592,536
														Subtotal = $592,536

Grand Total All Awards = $2,271,137

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DLL4 in the Developing Lung and Bronchopulmonary Dysplasia (BPD)

Award Number: R01HL162937

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2023

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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