Robert Lafyatis, MD
Campus: 3500 Terrace Street
Office: S720 BST
Pittsburgh, PA 15261
- B.S., Life Sciences, Massachusetts Institute of Technology
- B.S., Chemical Engineering, Massachusetts Institute of Technology
- M.D., University of Cincinnati College of Medicine
- Professor, Medicine
- Professor, Immunology
Our laboratory effort is focused on understanding scleroderma (systemic sclerosis), and developing novel therapeutic approaches based on identifying biomarkers of the disease process and utilizing biomarkers in clinical trials. We have utilized a biomarker approach in a clinical trial of fresolimumab (anti-TGF-beta) to show a role for TGF-beta in skin fibrosis associated with systemic sclerosis. We are also applying our pharmacodynamic biomarker of skin disease to trials of tocilizumab (trial completed), and C-82 and rilonacept (ongoing). Our group has particular interest in understanding the mechanisms stimulating immune response in systemic sclerosis, focusing on innate immune responses leading to fibrosis and vascular injury. Our data show increased expression of interferon responsive genes in circulating monocytes of scleroderma patients, prompting current investigations into the stimulus for this pattern of gene expression and the effect of interferon on fibrosis and vascular injury. Most recently, we have been examining the transcriptome of single cells in the skin and lungs of patients with systemic sclerosis to better understand changes in gene expression in different immune and connective tissue cell types that lead to disease.
To aid in developing new therapies for systemic sclerosis, we are studying the pathogenesis through existing murine models, particularly bleomycin-induced skin and lung fibrosis, testing novel therapeutics to clarify the relationship between innate immunity and fibrosis. Our goal is to gain insight from these models that will enable us to propose more informative early phase clinical trials, utilizing biomarkers to show target engagement and as a surrogate clinical response.
Stifano, G., Sornasse, T., Rice, L.M., Na, L., Chen-Harris, H., Khanna, D., Jahreis, A., Zhang, Y., Siegel, J., Lafyatis, R. Skin Gene Expression Is Prognostic for the Trajectory of Skin Disease in Patients With Diffuse Cutaneous Systemic Sclerosis. Arthritis Rheumatol. 2018; 70(6): 912-919.
Denton, C.P., Ong, V.H., Xu, S., Chen-Harris, H., Modrusan, Z., Lafyatis R., Khanna, D., Jahreis, A., Siegel, J., Sornasse, T. Therapeutic interleukin-6 blockade reverses transforming growth factor-beta pathway activation in dermal fibroblasts: insights from the faSScinate clinical trial in systemic sclerosis. Ann Rheum Dis. 2018; annrheumdis-2018-213031.
Fleury, M., Belkina, A.C., Proctor, E.A., Zammitti, C., Simms, R.W., Lauffenburger, D.A., Snyder-Cappione, J.E., Lafyatis, R., Dooms, H. Increased Expression and Modulated Regulatory Activity of Coinhibitory Receptors PD-1, TIGIT, and TIM-3 in Lymphocytes From Patients With Systemic Sclerosis. Arthritis Rheumatol. 2018; 70(4): 566-577.
Tabib, T., Morse, C., Wang, T., Chen, W., Lafyatis, R. SFRP2/DPP4 and FMO1/LSP1 Define Major Fibroblast Populations in Human Skin. J Invest Dermatol. 2018; 138(4): 139-146.
Sun, Z., Wang, T., Deng, K., Wang, X.F., Lafyatis, R., Ding, Y., Hu, M., Chen, W. DIMM-SC: a Dirichlet mixture model for clustering droplet-based single cell transcriptomic data. Bioinformatics. 2018; 34(1): 139-146.
Cascio, S., Medsger, T.A. Jr., Hawse, W.F., Watkins, S.C., Milcarek, C., Moreland, L.W., Lafyatis, R.A., Fuschiotti, P. 14-3-3z sequesters cytosolic T-bet, upregulating IL-13 levels in TC2 and CD8+ lymphocytes from patients with scleroderma. J Allergy Clin Immunol. 2017; S0091-6749(17): 31760-31768.
Lafyatis, R., Mantero, J.C., Gordon, J., Kishore, N., Carns, M., Dittrich, H., Spiera, R., Simms, R.W., Varga, J. Inhibition of ß-Catenin Signaling in the Skin Rescues Cutaneous Adipogenesis in Systemic Sclerosis: A Randomized, Double-Blind, Placebo-Controlled Trial of C-82. J Invest Dermatol. 2017; 137(12): 2473-2483.
Derrett-Smith, E.C., Martyanov, V., Chighizola, C.B., Moinzadeh, P., Campochiaro, C., Khan, K., Wood, T.A., Meroni, P.L., Abraham, D.J., Ong, V.H., Lafyatis, R., Whitfield, M.L., Denton, C.P. Limited cutaneous systemic sclerosis skin demonstrates distinct molecular subsets separated by a cardiovascular development gene expression signature. Arthritis Res Ther. 2017; 19(1): 156.
Cao, L., Lafyatis, R., Burkly, L.C. Increased dermal collagen bundle alignment in systemic sclerosis is associated with a cell migration signature and role of Arhgdib in directed fibroblast migration on aligned ECMs. PLoS One. 2017; 12(6): e0180751.
Makino, K., Makino, T., Stawski, L., Mantero, J.C., Lafyatis, R., Simms, R., Trojanowska, M. Blockade of PDGF Receptors by Crenolanib Has Therapeutic Effect in Patient Fibroblasts and in Preclinical Models of Systemic Sclerosis. J Invest Dermatol. 2017; 137(8): 1671-1681.