UPMC and Pitt Rheumatology Systemic Sclerosis Center of Research Translation NIH P50 Grant – Renewal Will Support New Scleroderma Translational Investigations

Along with a group of multidisciplinary collaborators, principal investigator Robert Lafyatis, MD, director of the Scleroderma Center at UPMC and the University of Pittsburgh, has been awarded a new National Institutes of Health P50 grant entitled “Clinical-Translational Studies in Skin, Lung, and Vascular Complications in Systemic Sclerosis.” This highly competitive grant award will enable Dr. Lafyatis and his assembled team of collaborators to continue the long-standing work of the Systemic Sclerosis Center of Research Translation that focuses on the pathophysiology of this debilitating disease, elucidation of biomarkers and potential molecular therapeutic targets, and engagement in clinical trials of promising agents that may modulate disease development, progression, or severity.

Joining Dr. Lafyatis as director are principal investigators of the new projects, Robyn T. Domsic, MD, MPH, associate professor of Medicine and clinical director of the Scleroderma Center; Stephen Y. Chan, MD, PhD, FAHA, professor of Medicine in the Division of Cardiology and director of the Vascular Medicine Institute and Center for Pulmonary Vascular Biology of Disease; Oliver Eickelberg MD, FERS, ATSF, vice chair for Basic and Translational Science in the Division of Pulmonary, Allergy, and Critical Care Medicine; and Harinder Singh, PhD, professor in the Department of Immunology at the University of Pittsburgh and director of the Center for Systems Immunology.

"We have a tremendous multidisciplinary team assembled," says Dr. Lafyatis. "And while we have our individual components and focused studies as part of the P50 grant, each of the collaborators is well-known and respected nationally in their respective fields. Our work with this grant is entirely translational in nature and focused on understanding scleroderma in human subjects, tissues, and cells.”

Overview of Investigations and their Objectives

Systemic sclerosis (SSc) is a multifaceted disease that can manifest a broad spectrum of symptoms and affect numerous organs – including the skin, lungs, heart, GI tract, and kidneys. The two primary causes of mortality in patients with SSc are interstitial lung disease (ILD) and pulmonary arterial hypertension, neither of which have therapeutics that can entirely halt or reverse the disease processes.

Dr. Eickelberg’s project will delve further into the proteomics and genomics of interstitial lung disease in SSc using powerful single-cell RNA sequencing techniques to characterize the nature of fibrotic lung tissues and identify potential protein targets that could be used as biomarkers of ILD or that may provide the basis for new drug developments targeting specific cellular proteins responsible for driving fibrotic changes in lung tissue. Dr. Eickelberg and Dr. Lafyatis also will collaborate on an observational clinical trial involving tocilizumab, an IL-6 receptor antagonist recently approved for treatment of scleroderma, to better understand its mechanisms of action.

Dr. Chan’s studies are focused on the pathways and mechanisms driving pulmonary arterial hypertension. Specifically, his laboratory is exploring the potential of a novel form of a PET CT imaging system employing a radionucleotide called 18F-fluroglutamine (18F-FGln) to more effectively detect and diagnose damage to blood vessels in the lungs of patients with SSc. The study may also shed important new light on how metabolic processes in platelets lead to blood vessel damage in the lungs. Dr. Chan's study of 18F-FGln will be the first of its kind conducted in humans.

Dr. Domsic will continue to oversee the clinical and biorepository core of the grant, which will help to curate crucial samples of blood, lung, and skin tissues from patients with SSc who have been enrolled in a now decades-long observational cohort registry. Importantly, this growing repository will also include new subjects undergoing lung transplantation and other forms of treatment for their SSc at UPMC. Dr. Domsic's expertise in clinical trials development and collection of registry data/biorepository samples will facilitate the other translational investigations that are part of the new P50.

Dr. Lafyatis' research on skin fibrosis in SSc and its accompanying consequences continues in the new P50. His well-known expertise in the use of single-cell sequencing will further be deployed to investigate how various cell types and their constituent proinflammatory and profibrotic nature lead to or influence mechanistic pathways responsible for skin fibrosis. Dr. Lafyatis will also collaborate with Kathryn Torok, MD, a pediatric rheumatologist at UPMC Children's Hospital of Pittsburgh, to study localized scleroderma affecting the skin in children.

Dr. Singh leads the systems biology core for the grant. His expertise in computational medicine, genomics, and machine learning modeling will support various data analysis, interpretation, and modeling of findings uncovered in the various experiments.

“Systemic sclerosis is acknowledged to be the most difficult rheumatologic disease to treat and study,” says Dr. Lafyatis. “Pittsburgh has an incredible track record in doing both, partly due to the exceptional talent that has come through these doors during the last 50 years, but also in part because of the collaborative, cross-disciplinary research we are able to conduct because of the resources, skills, and investments in research and clinical care that have materialized at UPMC and the University of Pittsburgh during that time. Our P50 is a great example of this dynamic.”

Learn more about the P50 grant and its research goals here.

More About the Division of Rheumatology and Clinical Immunology at UPMC and the University of Pittsburgh

UPMC and the University of Pittsburgh School of Medicine Division of Rheumatology and Clinical Immunology has built an internationally recognized tradition of excellence in patient care, education, and research over more than five decades. Clinical activities in the Division emphasize care of both common and rare rheumatic diseases, while a major research focus of the Division is to define fundamental processes that underlie mechanisms of autoimmunity and how these may ultimately be harnessed for patient benefit. Research strengths within the Division include basic mechanisms of tissue injury and pathogenesis as well as clinical features, natural history, and therapy of systemic sclerosis, systemic lupus erythematosus, polymyositis-dermatomyositis, rheumatoid arthritis, vasculitis, and osteoarthritis.

Learn more about the Division, its Clinical Centers of Excellence, and Research Laboratories here.