Thursday, September 21, 2023
9/21/2023
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 a-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 a-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-ß1. 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.
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