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Endothelial S1PR1 promotes lung repair in post-viral ARDS

Award Number: K01HL174822
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 08/01/2024
PERIOD OF PERFORMANCE END DATE: 07/31/2025
AWARD TERMINATION DATE: 06/16/2025

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Endothelial S1PR1 promotes lung repair in post-viral ARDS - Viral respiratory infections, such as influenza and SARS-CoV2, frequently lead to acute respiratory distress syndrome (ARDS), a condition with a mortality up to 46%. Endothelial injury, dysfunction and the resultant vascular hyperpermeability contribute to the severity of ARDS, persistence of lung injury, and dysregulated repair with the development of fibrosis. While sphingosine-1-phosphate receptor 1 (S1PR1) is a key protective signaling axis on endothelial cells, the role of S1PR1 signaling in the resolution of lung injury in post-viral ARDS has not been well explored. The objective of this application is to define endothelial S1PR1-dependant pathways which promote the re-alveolarization of the post-viral lung needed to prevent morbid fibrotic outcomes. We hypothesize that endothelial S1PR1 signaling promotes productive lung repair after viral infection via BMP2 mediated support of the epithelial niche. These preliminary findings a new facet to the pleotropic benefits of EC S1PR1 beyond its established role in limiting vascular hyperpermeability and highlight a need to comprehensively validate the therapeutic potential of augmenting S1PR1 expression to limit post-viral pulmonary fibrosis. We will test this hypothesis via two specific aims: 1) determine the mechanism of endothelial S1PR1 mediated epithelial repair after viral-induced ARDS, and 2) determine how EC S1PR1 regulation can be therapeutically augmented to attenuate post-viral fibrosis. The proposed research will reveal novel links between EC S1PR1 and epithelial regeneration and differentiation after viral infection and identify regulators of endothelial function which can be therapeutically targeted to attenuate post- viral fibrosis. Dr. Brazee’s long-term goal is to be an independent basic and translational investigator with a research program aimed at understanding the contributions of the endothelium in supporting productive lung repair pathways. The proposed K01 research aims utilize prior training in mouse models of influenza virus infection, fibrotic lung disease, and fundamental molecular biology techniques. In addition, the project will necessitate advanced training in vascular and epithelial biology, G-protein coupled receptor (GPCR) signaling, and translational modeling of human disease using human derived 3D organoids and precision cut lung slices. Successful completion of these aims, together with continued professional development, will provide the proficiencies necessary to establish a productive research program and an impactful career as an independent R01-funded investigator.


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 = $0 )
2026	2024	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Lung Diseases Research	000	1	1/18/2026	TERMINATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Lung Diseases Research	000	1	6/16/2025	TERMINATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $161,240 )
2024	2024	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Lung Diseases Research	000	1	7/24/2024	NEW	$161,240
														Subtotal = $161,240

Grand Total All Awards = $161,240

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Endothelial S1PR1 promotes lung repair in post-viral ARDS

Award Number: K01HL174822

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 08/01/2024

PERIOD OF PERFORMANCE END DATE: 07/31/2025

AWARD TERMINATION DATE: 06/16/2025

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