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. More recently, we have applied single cell technologies to understand the molecular changes in stromal and inflammatory cell populations in the skin and lungs of patients with systemic sclerosis. In the skin we have discovered changes in several fibroblast populations. One of these populations, DPP4/SFRP2-expressing fibroblasts differentiate in two steps into myofibroblasts. In ongoing studies, we are identifying the alterations in chromatin structure and transcription factors regulating myofibroblast differentiation. We have carried out similar studies analyzing lungs from patients with systemic sclerosis associated interstitial lung disease. These lungs also show an emergent population of myofibroblasts, with an overlapping but distinct phenotype compared to skin myofibroblasts. We have also characterized a population of macrophages associated with progressive interstitial lung disease. We are further studying the pathways driving differentiation of both of these cell populations using single cell ATAC-seq. We anticipate that these detailed molecular understandings and in further in silico analysis in collaboration with colleagues in systems biology will lead us to better understand the cytokines communicating between cell populations promoting fibrosis, and lead to new key targets for therapeutic intervention.
- B.S., Life Sciences, Massachusetts Institute of Technology, 1978
- B.S., Chemical Engineering, Massachusetts Institute of Technology, 1978
- M.D., University of Cincinnati College of Medicine, 1983
- Residency/Intern, Medicine, NC Baptist Hospital, Bowman-Gray School of Medicine, 1986
- Rheumatology Fellowship, National Institutes of Health, NIAMS, 1989
- Biotechnology Fellowship, National Institutes of Health, NCI, 1990
- Visiting Scientist, Institut Pasteur, France, 1991
Education & Training
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.
R01 DE029034, Treatment of Periodontitis by Homing M2 Macrophages, 2020-2025.
