A large duplication in the fibrillin-1 gene (Tsk fibrillin-1) is responsible for the phenotype of the Tsk mouse, a model for skin disease in human systemic sclerosis (SSc). The best defined function of fibrillin is in supporting elastic fibers and we have recently found that Tsk mice show markedly increased hypodermal elastic fibers associated with striking changes in fibulin-2 and fibulin-5, proteins that regulate formation of elastic fibers. We are investigating the hypotheses that altered hypodermal deposition of fibulins causes skin tethering in Tsk mice and that altered dermal fibulin deposition increases elastic fibers in human SSc. We will study the effect of Tsk fibrillin-1 on fibulin-2 and -5 matrices by staining cells conditionally expressing Tsk-fibrillin-1. We will test the importance of fibulin-2 on Tsk skin tethering and altered elastogenesis by breeding Tsk mice to fibulin-2 deleted mice, we will also study the effect of fibulin-2 on elastogenesis in fibroblasts overexpressing or deleted of fibulin-2 in cell culture. Fibrillin associates with several other matrix proteins, including MAGP-2. We have found markedly increased MAGP-2 matrix in the skin of Tsk mice and human SSc. Upon expression of Tsk fibrillin-1 in cell lines, we find increased MAGP-2 and collagen matrices, suggesting that Tsk fibrillin-1 might augment collagen deposition through increased MAGP-2. The effect of increased MAGP-2 expression on collagen, fibulin and elastic fiber matrices will be studied in cell lines and transgenic mice. TGF-beta may interact indirectly with fibrillin-1 through latent TGF-beta binding proteins and TGF-beta regulates fibrillin-1 and MAGP-2 matrices in vitro. Since these are features of Tsk dermal pathology, the importance of TGF-beta on the Tsk phenotype and altered elastogenesis will be tested by examining MAGP-2 and fibulin-2 expresssion in Tsk mice bred to smadS deleted or fibroblast-targeted TGF-beta Rll deleted mice. Fibroblast cultures from these mice will also be examined for alterations in TGF-beta activity, and MAGP-2 and fibulin-2 mRNA expression. LTBP-1 or LTBP-4 will be examined as possible mediators of Tsk fibrillin-1 activation of TGF-beta signaling. Together these studies should help clarify the pathogenesis of altered elastogenesis and fibrosis associated with Tsk fibrillin-1. These findings will be correlated with studies on human SSc skin.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR051089-05
Application #
7667176
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Tseng, Hung H
Project Start
2005-08-20
Project End
2011-04-30
Budget Start
2009-08-01
Budget End
2011-04-30
Support Year
5
Fiscal Year
2009
Total Cost
$198,091
Indirect Cost
Name
Boston University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Moll, Matthew; Christmann, Romy B; Zhang, Yuqing et al. (2018) Patients with systemic sclerosis-associated pulmonary arterial hypertension express a genomic signature distinct from patients with interstitial lung disease. J Scleroderma Relat Disord 3:242-248
Rice, Lisa M; Mantero, Julio C; Stratton, Eric A et al. (2018) Serum biomarker for diagnostic evaluation of pulmonary arterial hypertension in systemic sclerosis. Arthritis Res Ther 20:185
Rice, Lisa M; Mantero, Julio C; Stifano, Giuseppina et al. (2017) A Proteome-Derived Longitudinal Pharmacodynamic Biomarker for Diffuse Systemic Sclerosis Skin. J Invest Dermatol 137:62-70
Lafyatis, Robert; Mantero, Julio C; Gordon, Jessica et al. (2017) Inhibition of ?-Catenin Signaling in the Skin Rescues Cutaneous Adipogenesis in Systemic Sclerosis: A Randomized, Double-Blind, Placebo-Controlled Trial of C-82. J Invest Dermatol 137:2473-2483
Taroni, Jaclyn N; Greene, Casey S; Martyanov, Viktor et al. (2017) A novel multi-network approach reveals tissue-specific cellular modulators of fibrosis in systemic sclerosis. Genome Med 9:27
Urso, Katia; Alvarez, David; Cremasco, Viviana et al. (2016) IL4RA on lymphatic endothelial cells promotes T cell egress during sclerodermatous graft versus host disease. JCI Insight 1:
Ziemek, Jessica; Man, Ada; Hinchcliff, Monique et al. (2016) The relationship between skin symptoms and the scleroderma modification of the health assessment questionnaire, the modified Rodnan skin score, and skin pathology in patients with systemic sclerosis. Rheumatology (Oxford) 55:911-7
Sargent, Jennifer L; Li, Zhenghui; Aliprantis, Antonios O et al. (2016) Identification of Optimal Mouse Models of Systemic Sclerosis by Interspecies Comparative Genomics. Arthritis Rheumatol 68:2003-15
Christmann, Romy B; Wooten, Alicia; Sampaio-Barros, Percival et al. (2016) miR-155 in the progression of lung fibrosis in systemic sclerosis. Arthritis Res Ther 18:155
Nazari, Banafsheh; Rice, Lisa M; Stifano, Giuseppina et al. (2016) Altered Dermal Fibroblasts in Systemic Sclerosis Display Podoplanin and CD90. Am J Pathol 186:2650-64

Showing the most recent 10 out of 55 publications