Tuesday, August 19, 2025 8/19/2025

Interaction of fibroblasts with cell corpses increases collagen synthesis during lung repair

Award Number: R01HL166938
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2023
PERIOD OF PERFORMANCE END DATE: 06/30/2028

Group Awards By:

View Award Description

Interaction of fibroblasts with cell corpses increases collagen synthesis during lung repair - PROJECT SUMMARY Repair after injury is a fundamental biologic process that is critical for maintaining lung health. Fibroblasts must perform key pro-repair functions after injury including proliferation and synthesis of new extracellular matrix, particularly collagens, that scaffold wound closure. Dead cells (collectively termed cell corpses) are produced during lung injury and inflammation and have been shown to promote the transition from inflammation to repair. Prior research has focused on understanding macrophage interactions with apoptotic corpses. However, non- professional phagocytes including fibroblasts can also interact with cell corpses and the consequence of these interactions in the lung has not been studied. This proposal seeks to address unknowns regarding fibroblast- corpse interactions and their role in healthy lung repair. We have found that recognition of cell corpses by fibroblasts causes fibroblasts to increase collagen protein synthesis. Our preliminary data support a mechanism where the phosphatidylserine receptor Axl binds cells corpses, activates polyamine metabolite synthesis, increasing intracellular spermidine levels, which fuel hypusination. Hypusination occurs on a single protein: the ribosomal subunit eiF5a. When hypusinated, eiF5a is able to stabilize translation of poly-proline-repeat proteins including collagen. Hypusination is also important for cell proliferation. Blocking polyamine synthesis prevented hypusination of eiF5a in response to corpse recognition. Blocking Axl or hypusine-eiF5a prevented the increase in collagen in response to corpse recognition. We also show that, in vivo, hypusine-eiF5a is increased in fibroblasts after lung injury and that collagen deposition and alveolar-capillary repair are reduced when hypusination is blocked with the inhibitor GC7 or through targeted deletion of the hypusination enzyme deoxyhypusine synthase in fibroblasts. This led us to hypothesize that interaction of fibroblasts with cell corpses is a central cue that activates fibroblast proliferation and collagen synthesis following lung injury, facilitating repair. We will use three aims to test if 1) corpse recognition via Axl triggers a translationally-regulated increase in collagen protein, 2) corpse recognition drives polyamine synthesis that increases spermidine that increases hypusine-eiF5a and stabilizes collagen translation, and 3) to fully activate pro-repair programming fibroblasts require the ability to sense corpses via Axl, synthesize polyamines via ornithine decarboxylase, and hypusinate eiF5a via deoxyhypusine synthase in order to proliferate and synthesize new extracellular matrix after lung injury.


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 = $623,931 )
2025	2025	NATIONAL JEWISH HEALTH	1400 JACKSON ST	DENVER	CO	80206	DENVER	USA	Lung Diseases Research	000	3	7/2/2025	NON-COMPETING CONTINUATION	$623,931
														Subtotal = $623,931

Issue Date FY: 2024 ( Subtotal = $605,515 )
2024	2024	NATIONAL JEWISH HEALTH	1400 JACKSON ST	DENVER	CO	80206	DENVER	USA	Cardiovascular Diseases Research	000	2	6/26/2024	NON-COMPETING CONTINUATION	$605,515
														Subtotal = $605,515

Issue Date FY: 2023 ( Subtotal = $619,300 )
2023	2023	NATIONAL JEWISH HEALTH	1400 JACKSON ST	DENVER	CO	80206	DENVER	USA	Lung Diseases Research	000	1	6/5/2023	NEW	$619,300
														Subtotal = $619,300

Grand Total All Awards = $1,848,746

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Interaction of fibroblasts with cell corpses increases collagen synthesis during lung repair

Award Number: R01HL166938

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2023

PERIOD OF PERFORMANCE END DATE: 06/30/2028

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer