The overall goal of this Center of Research Translation is to utilize biomarker tools and other translational research observations to discover new therapies for patients with systemic sclerosis (SSc). This goal can be broken down into four intermediate objectives: understanding pathogenic pathways through translational studies, developing biomarkers for SSc, developing novel therapeutics, and applying bioinformatic and systems biology approaches to interpret translational and biomarker data. Among current obstacles to progress in finding new drugs for SSc patients is the continuing limited understanding of pathogenesis of SSc disease, in part due to its complexity and heterogeneity, and in part due to the lack of good animal models. Innovative protocols of University of Pittsburgh Medical Center and Boston University Medical Center for obtaining SSc skin and lung biosamples will allow investigators to discover the genes, regulatory proteins, mediators and cells that promote fibrosis and vascular injury in SSc patients. These include very large, longitudinal clinical-biological sample repositories; SSc lung transplant and warm autopsy programs; and skin biopsy, ex vivo lung perfusion, functional distal pulmonary arterial myography and lung explant culture protocols. In Project 1 investigators will validate biomarkers of SSc skin and lung disease, investigate mesenchymal cell heterogeneity in normal and SSc skin using single cell RNA-seq, and study the effect of blocking genes associated with myofibroblast differentiation. In Project 2 investigators will examine altered markers of oxidative stress and mitophagy in SSc leukocytes and pulmonary vascular endothelial cells obtained during right heart catheterization and from dissected pulmonary arteries of patients with SSc- associated pulmonary arterial hypertension. They will also investigate the effect of the recently approved Nrf2 inhibitor, dimethyl fumarate, on endothelial cells in these systems. In Project 3 investigators will study expression of ubiquitin ligases in SSc-associated interstitial lung disease (SSc-ILD). They will also design optimal ubiquitin ligase antagonists for SSc-ILD using quantitative structure-activity relationships, and test these inhibitors in lung explant and ex vivo lung perfusion models. Project aims will be supported by three resource cores: a Clinical and Biological Specimen Core, a Lung Tissue Core and a Translational Genomics and Data Integration Core. The latter will synthesize data from each project and across projects, to develop models for common molecular pathways associated with different disease manifestations. The focus of each of the projects on different SSc clinical manifestations, mediators of disease, and drug inhibitors will provide a rich, highly collaborative environment for fundamental discovery within bridging project topics and core resources. This will be further enhanced by the complementary experience of the project and core investigators in biosampling, biomarkers, translational medicine, drug development, bioinformatics and systems biology, culminating in the development of new, targeted therapeutics.
Systemic sclerosis (SSc) is a severe scarring disease that affects many organs including the skin and lungs. Skin disease is painful and disfiguring, while lung disease can be lethal. Currently there are no approved treatments for this disease. This grant will provide for a coordinated group of scientists to study SSc skin and lung scarring, and associated disease in blood vessels and white blood cells. The work will be highly aided by obtaining skin biopsies and diseased lung tissue from patients undergoing lung transplantation. Several hypotheses will be studied. By blocking specific signaling pathways that regulate cell differentiation, project scientists will seek to better understand how genes control scarring, white blood cells and blood vessel cells in these patients. Inhibitors that block disease-mediating pathways in tissues from SSc patients will be strong candidates to target with new medications.
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|Meiners, Silke; Evankovich, John; Mallampalli, Rama K (2018) The ubiquitin proteasome system as a potential therapeutic target for systemic sclerosis. Transl Res 198:17-28|
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|Cheong, Fei-Ying; Gower, Adam C; Farber, Harrison W (2017) Changes in gene expression profiles in patients with pulmonary arterial hypertension associated with scleroderma treated with tadalafil. Semin Arthritis Rheum 46:465-472|
|Yamashita, Takashi; Asano, Yoshihide; Taniguchi, Takashi et al. (2017) Glycyrrhizin Ameliorates Fibrosis, Vasculopathy, and Inflammation in Animal Models of Systemic Sclerosis. J Invest Dermatol 137:631-640|
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