Therapeutic Targeting of Arginine-Dependent Pulmonary Fibrosis
Abstract
Idiopathic pulmonary fibrosis (IPF) is a lung disease characterized by progressive tissue scarring of unknown causes. It is predicted to have a worse outcome than many cancers. Unfortunately, no reliable biomarkers and/or effective treatments are available to IPF patients. Accumulative evidences have indicated that glucose breakdown and amino acid (e.g., arginine) synthesis are dysregulated during the development and progression of IPF. With the hope of discovering a better treatment option for IPF patients and thus prolonging their life span, we need to sort out key players in biochemical reactions that would trigger and lead to abnormal wound healing response (fibrosis, also known as fibrotic scarring), which could guide us to identify promising targets for reversing lung scarring. By integrating and analyzing datasets of IPF metabolic signaling cascades, arginine succinate synthase (ASS1) expression is particularly altered in IPF lung fibroblasts. ASS1 is an enzyme of the urea cycle that controls the key step of converting the two amino acids, citrulline and aspartate, into arginine production. In addition, many studies have reported a loss of ASS1 expression in several advanced tumors, suggesting a worse outcome when this enzyme is inactivated during disease progression. Apart from cancer research, the role of ASS1 in contributing to IPF disease status has not yet been investigated. Interestingly, examples of metabolic enzyme have been shown to directly participate in cell signaling events governed by a group of cell surface receptors termed receptor tyrosine kinases (RTKs). We have identified the hepatocyte growth factor receptor (HGFR or c-Met) as the top one RTK receptor associated with ASS1 expression after screening an array of phospho-RTKs. HGFR phosphorylation has been well-documented in cancer studies where its activation can regulate signaling events to cause cancer cell growth and spread of cancerous tumors. In recent years, the activity of HGFR has been reported to be implicated in lung fibrosis; however, whether HGFR and its signaling pathways function in promoting fibroblast activation and conversion to a cell type (myofibroblast) that promotes fibrosis remains unknown. Our preliminary data have demonstrated that a decreased expression of ASS1 acts in parallel with an increased HGFR phosphorylation in IPF lung fibroblasts, implying an association of HGFR activity with ASS1 expression in the context of IPF. Based on the above observations, we hypothesize that ASS1 loss and/or downregulation activates lung fibroblasts and subsequent fibrotic progression through HGFR signaling. Direct targeting of lung fibroblast cells lacking ASS1 expression may attenuate HGFR-driven invasive growth and progression of IPF. The overall objective of this application is to determine whether ASS1 deficiency serves as a therapeutic target and to test if direct blockade of the uptake of extracellular arginine reduces accumulation of fibroblasts in the lung and suppresses collagen deposition. To this end, two specific aims are proposed. We first aim to characterize the specific contribution of ASS1 deficiency in the regulation of HGFR activity and lung fibroblast phenotypes (Aim 1). Next, we aim to confirm whether IPF lung fibroblasts exhibit an intrinsic dependence on extracellular arginine, making them sensitive to arginine deprivation, and also test if arginine blockade is a druggable strategy for suppressing lung fibrosis (Aim 2). This proposed study addresses the following research topics including 1) research into the pathobiology and molecular mechanisms underlying the development and progression of pulmonary fibrosis; and 2) development and/or testing of novel and/or innovative treatments, including precision medicine approaches, to delay or modify the progression of pulmonary fibrosis. A successful completion of our proposed aims will not only provide an evidence-based therapeutic potential but also demonstrate mechani
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110086
Entities
People
- Ching-hsien Chen
Organizations
- United States Army
- University of California, Davis