Organ fibrosis is an irreversible endpoint of several diseases, leading to organ failure. Systemic sclerosis (SSc) is a prototypic fibrotic disease with fibrosis affecting multiple organs including the lung. Currently the only available therapeutic option for patients with fibrosis is organ transplantation, which is clinically impossible on the scale necessary. The hallmark of fibrosis in multiple organs is the disruption of extracellular matrix (ECM) homeostasis, resulting in accumulation of ECM components and subsequent organ failure. Fibrosis is characterized by upregulation of fibrotic triggers such as connective tissue growth factor (CTGF), increase in the deposition of collagen, fibronectin and other ECM components, enhanced matrix crosslinking due to an increase in levels and activity of lysyl oxidase (LOX) enzyme, and decreased ECM degradation via reduced matrix metalloprotease (MMP) levels and activity. We identified a peptide derived from the carboxy terminal region of human endostatin, named E4, that exerts anti-fibrotic activity in vitro, ex vivo, and in vivo whether administered prior to, concomitantly with, or following a fibrotic trigger such as bleomycin or TGF?. Our recent findings described in the preliminary studies suggest that E4 activates the urokinase pathway via increasing urokinase plasminogen activator (uPA) levels and activity and decreasing those of its inhibitor PAI-1. Mechanistically, E4 engages uPAR and phosphorylated ?-catenin in fibroblast membranes. E4 also decreases Egr-1 levels and increases nuclear levels of Pax6. We propose to 1) determine the role of ?-catenin/E4 and uPAR/E4 interactions in mediating the anti-fibrotic effects of E4, 2) define the role of phosphorylated ?-catenin and its reduced nuclear translocation in mediating the effects of E4, and 3) investigate the role of the transcription factors Egr-1 and Pax6 downstream of E4. The beneficial effect of E4 in multiple pre-clinical models of lung fibrosis emphasizes its relevance to human disease. Our goal is to advance mechanistic knowledge of E4, which will allow for the identification of potential biomarkers and any possible side effects while facilitating further improvement of the peptide as a therapy.

Public Health Relevance

Relevance to Public Health: Organ fibrosis is responsible for fatal organ failure in millions of patients in the U.S. and worldwide. Systemic sclerosis (SSc) is the prototypic fibrotic disease. There is no effective therapy for organ fibrosis, but we have identified a novel peptide with anti-fibrotic activity that is effective at blocking and reversing fibrosis in two organs, lung and skin, including in human tissues. The successful completion of this work will help to elucidate mechanisms by which this peptide can improve fibrosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL121262-03
Application #
9610673
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Vuga, Louis J
Project Start
2017-01-01
Project End
2020-12-31
Budget Start
2019-01-01
Budget End
2019-12-31
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Medical University of South Carolina
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29407
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Garrett, Sara M; Frost, DeAnna Baker; Feghali-Bostwick, Carol (2017) The mighty fibroblast and its utility in scleroderma research. J Scleroderma Relat Disord 2:69-134
Watanabe, Tomoya; Nishimoto, Tetsuya; Mlakar, Logan et al. (2017) Optimization of a murine and human tissue model to recapitulate dermal and pulmonary features of systemic sclerosis. PLoS One 12:e0179917