- The principal investigator's long-term objective is to understand the regulation of ECM production by human fibroblasts and its dysregulation in fibrotic diseases such as scleroderma (SSc). Substantial evidence has accumulated in recent years that implicates transcriptional activation of collagen genes as a key component in development of fibrosis in SSc and other fibrotic diseases. Lesional SSc fibroblasts maintain an activated phenotype during propagation in culture, thus providing an accessible system to study the molecular mechanisms responsible for the elevated expression of collagen genes. Data generated during the last funding period together with work by others reveal that SSc and normal fibroblasts respond differently to exogenous signals transmitted by cytokines as well as integrins. In addition, the principal investigator has recently identified transcription factors Sp1 and Sp3 as central regulators of the COL1A2 gene transcription. More importantly, the principal investigator has shown that Sp1 and Sp3 not only contribute to the basal expression level but can elicit inductive responses to serum and at least one cytokine, Oncostatin M. These results enable the principal investigator to propose a much more complete model for collagen gene regulation, in which intersecting cytokine and integrin signaling pathways exert induction or repression effects through a limited number of transcription factors. Dysregulated response to these signaling pathways likely underlies the elevated levels of collagen gene expression in SSc. This model thus provides the basis for unraveling the complex molecular mechanism responsible for abnormal regulation of collagen genes in SSc fibroblast.
Four specific aims are proposed: 1) To identify the cis-regulatory elements and to characterize levels and activities of the cognate transcription factors in the COL1A2 promoter responsible for the different regulation of basal and cytokine (TGF-beta, OSM) stimulated collagen gene transcription in SSc and normal fibroblasts; 2) to characterize cis-regulatory elements in the human COL1A2 promoter mediating integrin modulation of the collagen gene transcription in SSc and normal fibroblasts; 3) to identify and characterize additional trans-acting factors involved in regulation of the human COL1A2 promoter activity, and 4) to characterize intracellular signaling pathways mediating cytokine and integrin regulation of collagen production in SSc and normal fibroblasts.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR042334-08
Application #
6374973
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Gretz, Elizabeth
Project Start
1994-08-10
Project End
2003-03-31
Budget Start
2001-08-01
Budget End
2003-03-31
Support Year
8
Fiscal Year
2001
Total Cost
$197,202
Indirect Cost
Name
Medical University of South Carolina
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
Stawski, Lukasz; Marden, Grace; Trojanowska, Maria (2018) The Activation of Human Dermal Microvascular Cells by Poly(I:C), Lipopolysaccharide, Imiquimod, and ODN2395 Is Mediated by the Fli1/FOXO3A Pathway. J Immunol 200:248-259
Toyama, Tetsuo; Looney, Agnieszka P; Baker, Brendon M et al. (2018) Therapeutic Targeting of TAZ and YAP by Dimethyl Fumarate in Systemic Sclerosis Fibrosis. J Invest Dermatol 138:78-88
Stawski, Lukasz; Trojanowska, Maria (2018) Oncostatin M and its role in fibrosis. Connect Tissue Res :1-10
Makino, Katsunari; Makino, Tomoko; Stawski, Lukasz et al. (2017) Anti-connective tissue growth factor (CTGF/CCN2) monoclonal antibody attenuates skin fibrosis in mice models of systemic sclerosis. Arthritis Res Ther 19:134
Takahashi, Takehiro; Asano, Yoshihide; Sugawara, Koji et al. (2017) Epithelial Fli1 deficiency drives systemic autoimmunity and fibrosis: Possible roles in scleroderma. J Exp Med 214:1129-1151
Farina, Antonella; Peruzzi, Giovanna; Lacconi, Valentina et al. (2017) Epstein-Barr virus lytic infection promotes activation of Toll-like receptor 8 innate immune response in systemic sclerosis monocytes. Arthritis Res Ther 19:39
Yamashita, Takashi; Asano, Yoshihide; Taniguchi, Takashi et al. (2017) Glycyrrhizin Ameliorates Fibrosis, Vasculopathy, and Inflammation in Animal Models of Systemic Sclerosis. J Invest Dermatol 137:631-640
Grzegorzewska, Agnieszka P; Seta, Francesca; Han, Rong et al. (2017) Dimethyl Fumarate ameliorates pulmonary arterial hypertension and lung fibrosis by targeting multiple pathways. Sci Rep 7:41605
Looney, Agnieszka P; Han, Rong; Stawski, Lukasz et al. (2017) Synergistic Role of Endothelial ERG and FLI1 in Mediating Pulmonary Vascular Homeostasis. Am J Respir Cell Mol Biol 57:121-131
Makino, Katsunari; Makino, Tomoko; Stawski, Lukasz et al. (2017) Blockade of PDGF Receptors by Crenolanib Has Therapeutic Effect in Patient Fibroblasts and in Preclinical Models of Systemic Sclerosis. J Invest Dermatol 137:1671-1681

Showing the most recent 10 out of 70 publications