Thursday, July 3, 2025 7/3/2025

Metabolic regulation of fibroblast fate by ATP citrate lyase

Award Number: F31HL158230
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 12/01/2021
PERIOD OF PERFORMANCE END DATE: 11/30/2023

Group Awards By:

View Award Description

Metabolic regulation of fibroblast fate by ATP citrate lyase - Project Summary Idiopathic Pulmonary Fibrosis (IPF) is a fibrotic lung disease characterized by progressive accumulation of fibrotic extracellular matrix (ECM) eventually leading to extensive airway remodeling, impaired lung function and respiratory failure. The cell type responsible for the majority of ECM production is an activated fibroblast known as the myofibroblast, characterized by α-SMA expression and production of ECM proteins, particularly collagen and fibronectin. Our laboratory has previously demonstrated that young mice are capable of spontaneously resolving bleomycin induced lung fibrosis, with the myofibroblast population undergoing apoptosis and clearance; in contrast, aged mice fail to resolve in association with a persistent myofibroblast population that appears to be resistant to apoptosis. ATP Citrate Lyase (ACLY) is an enzyme which catalyzes citrate to acetyl CoA conversion, thereby regulating acetyl-CoA bioavailability and fatty acid synthesis. Interrogation of a publicly available dataset indicates that ACLY mRNA levels are reduced in lungs of human subjects with IPF. Our preliminary data shows that ACLY expression in mice aged over 18 months is also deficient and that this expression decreases when subjected to bleomycin induced fibrogenesis. ACLY siRNA knockdown in IMR90 human fibroblasts promotes production of α-SMA, a myofibroblast marker, downregulates phosphorylation of AMPK and enhances myofibroblast apoptosis resistance. This project proposal will test the hypothesis that ACLY deficiency drives myofibroblast apoptosis regulation and determine whether ACLY is a therapeutic target in a mouse model of persistent lung fibrosis. Aim 1 will investigate ACLY regulation during myofibroblast differentiation, particularly its interaction with TGF-β1. Aim 2 will focus describing the mechanism of apoptotic regulation by ACLY, especially on its effects on AMPK phosphorylation. Aim 3 will make use of a genetic knockout mouse model to definitively examine whether ACLY deficiency is a key fibrotic driver capable of sustaining persistent fibrosis. Collectively these studies will elucidate the role ACLY in fibrogenesis and non-resolving persistent lung fibrosis while also serving as the vehicle for a solid foundation of research training for Samuel Smith (PI) under the mentorship of Dr. Victor Thannickal, fostering his professional development and facilitating his pathway to independent academic research.


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: 2024 ( Subtotal = -$99 )
2024	2023	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Lung Diseases Research	000	2	9/23/2024	NON-COMPETING CONTINUATION	-$99
														Subtotal = -$99

Issue Date FY: 2023 ( Subtotal = $38,984 )
2023	2023	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Lung Diseases Research	001	2	3/14/2023	NON-COMPETING CONTINUATION	$942
2023	2023	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Lung Diseases Research	000	2	1/12/2023	NON-COMPETING CONTINUATION	$38,042
														Subtotal = $38,984

Issue Date FY: 2021 ( Subtotal = $37,326 )
2021	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Lung Diseases Research	001	1	5/28/2021	NEW	$0
2021	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Lung Diseases Research	000	1	5/28/2021	NEW	$37,326
														Subtotal = $37,326

Grand Total All Awards = $76,211

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Metabolic regulation of fibroblast fate by ATP citrate lyase

Award Number: F31HL158230

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 12/01/2021

PERIOD OF PERFORMANCE END DATE: 11/30/2023

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer