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Regulation of lipid metabolism in pulmonary Type 2 cells

Award Number: R01HL148774
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/20/2021
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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Regulation of lipid metabolism in pulmonary Type 2 cells - Surfactant insufficiency compromises pulmonary compliance and respiratory function in multiple pulmonary pathologies. Our understanding of surfactant metabolism in adult pulmonary disease is very limited and this restricts the potential for therapeutic targeting. In this project, we have generated a new genetic model of surfactant insufficiency in adult disease by deleting the low-density lipoprotein receptor related protein 1 (LRP1) specifically in surfactant producing type 2 cells (AEC2). LRP1 functions as lipoprotein receptor and extracellular protease clearing receptor and it is associated with decreased respiratory function in patients with COPD and pulmonary arterial hypertension. Studies in our generated cell line of LRP1 knockdown AEC2 (LRP1 KD) and tamoxifen-inducible AEC2-specific LRP1 knockout mice (SPC-LRP1-/-) show that LRP1 is required to maintain surfactant lipid secretion and intracellular lipid homeostasis to ensure optimal pulmonary compliance and respiratory function. We hypothesize that LRP1 controls surfactant metabolism in AEC2 and we will study the regulatory mechanisms. In Aim 1 we will decipher the mechanism of action of LRP1 at the membrane level in AEC2 and its regulation of the lipid source for surfactant synthesis in AEC2. In Aim 2 we will investigate the epithelial to mesenchymal cross talk and the role of LRP1 in the progressive decline in lung function during profibrotic challenges and molecular mechanisms responsible. We will attempt a new therapeutic approach to stop the decline. This proposal is innovative conceptually and technically. The role of AEC2 lipid metabolism during adult pulmonary disease is unknown. LRP1 regulates many cellular functions through lipid metabolism in different tissues and our study shows that it also regulates pulmonary function through surfactant lipid metabolism. In addition, we use novel techniques that include inducible and cell-specific genetic knockout models in vivo lipid tracing and -omics analysis. Surfactant homeostasis enables basic pulmonary function, but the regulation of surfactant homeostasis in adult disease is very little understood. The significance of this research is further underscored by the fact that surfactant lipid is altered in multiple pulmonary pathologies, including the most prevalent ones.


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 = $515,294 )
2025	2025	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	450 CLARKSON AVE	BROOKLYN	NY	11203	KINGS	USA	Lung Diseases Research	001	4	2/25/2025	NON-COMPETING CONTINUATION	$0
2025	2025	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	450 CLARKSON AVE	BROOKLYN	NY	11203	KINGS	USA	Lung Diseases Research	000	4	11/6/2024	NON-COMPETING CONTINUATION	$515,294
														Subtotal = $515,294

Issue Date FY: 2024 ( Subtotal = $556,622 )
2024	2024	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	450 CLARKSON AVE	BROOKLYN	NY	11203	KINGS	USA	Lung Diseases Research	000	3	12/15/2023	NON-COMPETING CONTINUATION	$511,184
2024	2024	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	450 CLARKSON AVE	BROOKLYN	NY	11203	KINGS	USA	Lung Diseases Research	001	3	6/26/2024	NON-COMPETING CONTINUATION	$45,438
														Subtotal = $556,622

Issue Date FY: 2023 ( Subtotal = $566,268 )
2023	2023	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	450 CLARKSON AVE	BROOKLYN	NY	11203	KINGS	USA	Lung Diseases Research	000	2	11/25/2022	NON-COMPETING CONTINUATION	$509,641
2023	2023	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	450 CLARKSON AVE	BROOKLYN	NY	11203	KINGS	USA	Lung Diseases Research	001	2	3/6/2023	NON-COMPETING CONTINUATION	$56,627
														Subtotal = $566,268

Issue Date FY: 2022 ( Subtotal = $562,555 )
2022	2022	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	450 CLARKSON AVE	BROOKLYN	NY	11203	KINGS	USA	Lung Diseases Research	000	1	12/17/2021	NEW	$562,555
														Subtotal = $562,555

Grand Total All Awards = $2,200,739

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Regulation of lipid metabolism in pulmonary Type 2 cells

Award Number: R01HL148774

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/20/2021

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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