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Principal Investigator: ROBERT A. LAFYATIS
Organization: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
Fiscal Year: 2024
Award: $1,563,264
Funding agency: National Institute of Arthritis and Musculoskeletal and Skin Diseases
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,
identifying informative biomarkers for SSc complications, applying bioinformatics and systems biology
approaches to interpret translational and biomarker data, and developing novel targeted therapeutics. Among
current obstacles to progress in finding new drugs for SSc patients is the continuing limited understanding of
SSc pathogenesis, in part due to its complexity and heterogeneity, and in part due to the lack of good animal
models. The University of Pittsburgh School of Medicine stands in a unique position for informative translational
studies into SSc due to special resources and intellectual talent. It has very large, longitudinal clinical-biological
SSc repositories in rheumatology and pulmonary divisions; it has the only large national experience in single
cell studies in both SSc skin and lungs; it has a strong experience in studying lung proteomics; it has pulmonary
experts in modeling lung disease using in vitro precision cut lung slices and ex vivo lung perfusion; it has a
highly sophisticated program studying pediatric localized scleroderma, as well as pediatric SSc; it has an
experienced and innovative systems biology group; and it has a vigorous drug discovery platform. In Project 1
investigators will expand preliminary observations using single cell RNA-seq, to understand the transcription
factors (TFs) associated with myofibroblast differentiation and discover latent factors/cytokine mediating
macrophage-fibroblast interaction in SSc and pediatric LS. In Project 2 investigators will examine the genomic
and proteomic landscape of patients with SSc-associated interstitial lung disease. Project 2 will also screen
and carry out preclinical studies of Smad3 translocation inhibitors using precision cut lung slices. In Project 3
investigators will study altered platelet energetics and utilize 18F-fluoroglutamine PET imaging to understand
the role of metabolic reprogramming and glutaminolysis in SSc-associated pulmonary arterial hypertension.
Project aims will be supported by two resource cores: a Clinical and Biospecimen Core and a Systems Biology
Core. The former will include collecting comprehensive clinical data, acquiring skin biopsies and lung explant
tissue, and preparing precision cut lung slices. The latter will use a broad range of bioinformatics tools, including
novel methods for detecting stereospecific TF binding sites, and for discovering latent factors mediating cell-
cell interactions in scRNA-seq/multiome datasets. The Systems Biology Core will also synthesize proteomic
and genomic data in project 2, and integrate 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.
Terms: <1-Phosphatidylinositol 3-Kinase><Affect><Animal Model><Animal Models and Related Studies><Autoimmune Diseases><Automobile Driving><B cell differentiation factor><B cell stimulating factor 2><B-Cell Differentiation Factor><B-Cell Differentiation Factor-2><B-Cell Stimulatory Factor-2><BCDF><BSF-2><BSF2><Basal Transcription Factor><Basal transcription factor genes><Binding Sites><Bio-Informatics><Bioinformatics><Biologic Models><Biological><Biological Markers><Biological Models><Biology><Blood><Blood Platelets><Blood Reticuloendothelial System><Blood Vessels><Body Tissues><Breast Cell Glutaminase><Business-Friendly Atmosphere><Cell Body><Cell Communication><Cell Energetics><Cell Interaction><Cell-to-Cell Interaction><Cells><Center for Translational Science Activities><Childhood><Chromatin><Circumscribed Scleroderma><Clinical><Clinical Data><Clinical Trials><Combining Site><Connective Tissue><Cutaneous Disorder><Cutaneous sclerosis><Data><Data Bases><Data Set><Databases><Dermatologic biopsy><Dermatoses><Development><Disease><Disease Marker><Disease Pathway><Disorder><Drugs><EC 3.5.1.2><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Fibroblasts><Fibrosis><GA Protein><Gene Expression><General Transcription Factor Gene><General Transcription Factors><Genomics><Gln><Glutaminase><Glutamine><Goals><HPGF><Hepatocyte-Stimulating Factor><Heterogeneity><Hybridoma Growth Factor><IFN-beta 2><IFNB2><IL-6><IL6 Protein><In Vitro><Interleukin-6><Intermediary Metabolism><Interstitial Lung Diseases><Investigators><L glutamine amidohydrolase><L-Glutamine><Lead><Liver Glutaminase><Localized scleroderma><Lung><Lung Diseases><Lung Grafting><Lung Parenchyma><Lung Respiratory System><Lung Tissue><Lung Tissue Fibrosis><Lung Transplantation><MGI-2><Macrophage><Marrow platelet><Mediating><Mediator><Medical center><Medication><Metabolic><Metabolic Processes><Metabolism><Model System><Modeling><Molecular><Multiomic Data><Myeloid Differentiation-Inducing Protein><Myofibroblast><Mφ><Observation research><Observation study><Observational Study><Observational research><Organ><Oxidative Phosphorylation><Oxidative Phosphorylation Pathway><PET><PET Scan><PET imaging><PETSCAN><PETT><PI-3 Kinase><PI3-Kinase><PI3CG><PI3KGamma><PI3k><PIK3><PIK3CG><PIK3CG gene><Pathogenesis><Pathogenicity><Pathologic Processes><Pathological Processes><Pathway interactions><Patients><Pb element><Perfusion><Pharmaceutical Preparations><Phenotype><Phosphatidylinositol 3-Kinase><Phosphatidylinositol-3-OH Kinase><Phosphoinositide 3-Hydroxykinase><Plasmacytoma Growth Factor><Platelets><Population><Position><Positioning Attribute><Positron Emission Tomography Medical Imaging><Positron Emission Tomography Scan><Positron-Emission Tomography><Process><Proteomics><Protocol><Protocols documentation><PtdIns 3-Kinase><Pulmonary Diseases><Pulmonary Disorder><Pulmonary Fibrosis><Pulmonary Graft><Pulmonary Transplant><Pulmonary Transplantation><Q Levoglutamide><Q. Levoglutamide><Rad.-PET><Reactive Site><Regulatory Protein><Research Personnel><Research Resources><Researchers><Resources><Rheumatology><Role><Sclerosis><Serum Markers><Single-Nucleus Sequencing><Skin><Skin Diseases><Skin Diseases and Manifestations><Skin Tissue><Slice><Structure of parenchyma of lung><Systemic Scleroderma><Systemic Sclerosis><Systems Biology><Talents><Technology><Testing><Thrombocytes><Tissues><Transcription Factor Proto-Oncogene><Transcription factor genes><Translational Research><Translational Science><Type I Phosphatidylinositol Kinase><Type III Phosphoinositide 3-Kinase><Universities><Vacuolar Protein Sorting><autoimmune condition><autoimmune disorder><autoimmunity disease><bio-informatics tool><bio-markers><biobank><bioinformatics tool><biologic><biologic marker><biomarker><biorepository><business-friendly environment><cell type><clinical translation><clinically translatable><collaborative atmosphere><collaborative environment><cutaneous biopsy><cutaneous disease><cutaneous tissue><cytokine><data base><data integration><depository><dermal disease><dermal disorder><dermal sclerosis><detection method><detection procedure><detection technique><developmental><discover genes><disease of the lung><disorder of the lung><driving><drug discovery><drug/agent><epigenetically><epigenomics><experience><fibrosis in the lung><gene discovery><genetic regulatory protein><genomic data><genomic data-set><genomic dataset><global gene expression><global transcription profile><heavy metal Pb><heavy metal lead><human disease><human tissue><imaging approach><imaging based approach><inhibitor><injury to the vasculature><innovate><innovation><innovative><interactive atmosphere><interactive environment><interdisciplinary atmosphere><interdisciplinary environment><interferon beta 2><lung disorder><lung fibrosis><lung transplant><medical college><medical schools><model of animal><multiomics><multiple omic data><multiple omics><new drug target><new drug treatments><new druggable target><new drugs><new marker><new pharmacological therapeutic><new pharmacotherapy target><new therapeutic target><new therapeutics><new therapy><new therapy target><next generation therapeutics><novel><novel biomarker><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel marker><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel pharmacotherapy target><novel therapeutic target><novel therapeutics><novel therapy><novel therapy target><panomics><pathway><pediatric><peer-group atmosphere><peer-group environment><positron emission tomographic (PET) imaging><positron emission tomographic imaging><positron emitting tomography><pre-clinical study><preclinical study><profibrotic fibroblast><programs><progressive systemic sclerosis><protein expression><pulmonary><pulmonary arterial hypertension><pulmonary artery hypertension><regulatory gene product><repository><sNuc-Seq><scRNA-seq><school of medicine><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell technology><single cell transcriptomic profiling><single nucleus RNA-sequencing><single nucleus seq><single-cell RNA sequencing><single-nucleus RNA-seq><skin biopsy><skin disorder><skin sclerosis><snRNA sequencing><snRNA-seq><social role><specific biomarkers><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic target><tool><transcription factor><transcriptome><transcriptomics><translation research><translational investigation><translational research center><translational sciences center><translational study><vascular><vascular injury>