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In 2017, Robert A. Lafyatis, MD, professor of medicine and director of the UPMC and University of Pittsburgh Scleroderma Center received P50 funding1 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) for translational research into the pathogenesis and identification of novel targeting pathways in systemic sclerosis. The current NIH grant is a continuation of the P50 research Dr. Lafyatis has been conducting on systemic sclerosis since 2011, and builds upon many of the findings of his research to date, which includes the discovery of biomarkers associated with skin and interstitial lung disease (ILD) in SSc.
Dr. Lafyatis is an internationally recognized expert and research leader in the field of systemic sclerosis with a focus on the pathogenesis of the disease, as well as the identification of biomarkers associated with aspects of SSc and translational investigations of potential new therapeutic agents. Prior to joining UPMC and the University of Pittsburgh in 2015, Dr. Lafyatis held appointments at Boston University.
The ultimate goal of this continuing research is to translate research findings into potential new therapies for patients with SSc. "There are a number of aspects of this grant that are novel, such as the use of human samples harvested from lung transplant patients and derived from pulmonary hypertension arterial catheterization procedures, and new technology and biochemical approaches," says Dr. Lafyatis.
Research Details and Project Components
Dr. Lafyatis' current grant is a multifocal project consisting of three separate yet related lines of investigation. Multiple departments and laboratories at the University of Pittsburgh are collaborating on the studies, as are several of Dr. Lafyatis' former colleagues at Boston University.
The first aspect of the project will examine a variety of prognostic biomarkers related to disease pathogenesis and progression or manifestation of skin fibrosis and interstitial lung disease in SSc. Prior work by Dr. Lafyatis has implicated several genes and their expression in mesenchymal cells in the progression of both skin and lung fibrosis. Dr. Lafyatis also is interested in the role of transforming growth factor beta in disease pathogenesis and its effect on regulating myofibroblast differentiation. Using the relatively new technique of single-cell RNA sequencing, Dr. Lafyatis' colleagues will be able to probe the variations between mesenchymal cells in normal skin and that of fibrotic skin in SSc. The research also will examine the effects on myofibroblast differentiation and gene expression regulating the process by selectively blocking or knocking out the suspect genes in disease models or in human tissues.
In the second study, Dr. Lafyatis and colleagues at Boston University are further examining the role that oxidative stress and mitophagy plays in T cells in relation to pulmonary arterial hypertension (PAH) in systemic sclerosis. "Part of this study, and a novel approach at that, is the derivation of human tissue samples of the pulmonary artery from patients undergoing pulmonary arterial catheterization procedures. This approach will allow the researchers to collect these tissues and afford the ability to characterize those cells using the single- cell RNA sequencing technology we are using in other aspects of our research," says Dr. Lafyatis. A second aspect of this research into pulmonary arterial hyper.tension in SSc will examine the efficacy and effects of a newly approved agent, dimethyl fumarate2 (which has been used in the past to treat plaque psoriasis and more recently multiple sclerosis) on pulmonary arterial endothelial cells.
The final aspect of the current P50 grant is devoted to better understanding interstitial lung disease in SSc. Collaborating with the University of Pittsburgh Division of Pulmonary, Allergy, and Critical Care Medicine and its chief, Rama K. Mallampalli, MD, Dr. Lafyatis and coinvestigators from the Division are examining the role of ubiquitin ligase (UL) proteins in ILD, an area of investigation for which the Division has significant expertise. UL proteins regulate numerous biochemical processes, and their role in SSc-ILD is now coming to light. Because of the history, size, and expertise of the lung transplant program at the University of Pittsburgh, a unique aspect of this part of the study will be the harvesting of lung tissues from transplant patients who have systemic sclerosis. Using lung explant and ex vivo lung perfusion models, researchers will have access to what would otherwise be extremely difficult tissues to obtain.
"This particular grant is really designed to use human materials and apply a variety of exciting new technologies and biochemical approaches to help us find new therapies for SSc," says Dr. Lafyatis.
References and Further Reading
1. Translational Studies for Identifying and Targeting Novel Pathways in Systemic Sclerosis Pathogenesis. Project Number: 2 P50 AR060780 06A1. Funding Body: National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS). Principal Investigator: Robert A. Lafyatis. 2. Dimethyl Fumarate in Systemic Sclerosis-Associated Pulmonary Arterial Hypertension. Project Number: 5R21AR069285-02. Funding Body: National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS). Principal Investigators: Robert A. Lafyatis and Paul M. Hassoun.