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Reparative functions of human airspace macrophage subsets

Award Number: R01HL168278
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/15/2024
PERIOD OF PERFORMANCE END DATE: 06/30/2029

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Reparative functions of human airspace macrophage subsets - PROJECT SUMMARY For lung health to be restored after inflammation, dead cells must be removed from the airspaces and the alveolar epithelium must be repaired. Airspace macrophages (AM) have been implicated in clearance of apoptotic cells, termed efferocytosis, and in orchestrating epithelial repair. Whether all AM are capable of these functions, or whether distinct subsets perform specialized roles following inflammation is poorly understood. In previous studies, we leveraged an endobronchial lipopolysaccharide (LPS)-challenge model of acute lung inflammation in healthy adults to obtain human AM and investigate their transcriptional signatures. Using single cell RNA sequencing, we discovered that after exposure to LPS, the airspaces are dominated by recruited AM. These recruited AM can be divided into two discrete subsets based, in part, on their efferocytic and reparative signatures. However, the causal mechanism by which efferocytosis is linked to reparative programing of AM in humans has not been established. The primary objective of this proposal is to identify the unique functions and molecular drivers of AM subsets during resolution of inflammation and active lung repair. Based on analysis of transcriptional signatures and our prior studies, we postulate that a subset of AM that closely resemble interstitial macrophages (imAM) are characterized by two unique functions. First, we propose that imAM are uniquely programed for efferocytosis. Second, we hypothesize that imAM drive repair of the alveolar epithelium through production of paracrine signaling molecules. The proposed studies will independently test the dependence of efferocytosis on driving these functions. We will use primary AM obtained from endobronchial LPS-challenge of research participants and cutting-edge organotypic co-culture systems in the following three Specific Aims: 1) Test the hypothesis that imAM are specialized for efferocytosis. 2) Test the hypothesis that imAM promote alveolar epithelial repair. 3) Determine whether efferocytosis is required for reparative programing of human AM.


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 = $602,955 )
2025	2025	NATIONAL JEWISH HEALTH	1400 JACKSON ST	DENVER	CO	80206	DENVER	USA	Lung Diseases Research	000	2	7/11/2025	NON-COMPETING CONTINUATION	$602,955
														Subtotal = $602,955

Issue Date FY: 2024 ( Subtotal = $602,955 )
2024	2024	NATIONAL JEWISH HEALTH	1400 JACKSON ST	DENVER	CO	80206	DENVER	USA	Lung Diseases Research	000	1	7/12/2024	NEW	$602,955
														Subtotal = $602,955

Grand Total All Awards = $1,205,910

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Reparative functions of human airspace macrophage subsets

Award Number: R01HL168278

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/15/2024

PERIOD OF PERFORMANCE END DATE: 06/30/2029

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