The overall goal of our research is to understand the molecular mechanisms that underlie pathologic manifestations of scleroderma (SSc). Our studies have focused on delineating the role of a transcription factor, Fli-1, in SSc fibrosis. These studies have led to important new findings that not only established a key role for Fli-1 in regulating collagen homeostasis in healthy tissues, but also provided the evidence for the contribution of Fli-1 in deregulating matrix production in SSc. We demonstrated that Fli-1 is a potent repressor of interstitial collagen and other matrix protein genes, both in cultured human fibroblasts and in the mouse skin in vivo. Importantly, we found that Fli-1 functions as an antagonist of TGF-2 signaling and, therefore, a reduction of Fli-1 expression levels mimics TGF-2-induced gene program. We uncovered a novel mechanism whereby TGF-2 abrogates inhibitory effects of Fli-1 through PCAF-mediated acetylation. Fli-1 is consistently downregulated in SSc skin fibroblasts, supporting the notion that its absence may directly contribute to activation of SSc fibroblasts and uncontrolled matrix deposition in SSc skin in vivo. Fli-1 is also prominently expressed in endothelial cells (ECs) and pericytes in healthy skin, whereas it is significantly reduced in SSc vessels even in the early stages of the disease. The specific role of Fli1 in normal adult vessels is currently unknown;however, our preliminary results suggest that Fli-1 regulates a subset of genes that are involved in maintaining vessel homeostasis. On the other hand, downregulation of Fli-1 correlates with vascular remodeling. Furthermore, these studies suggest that Fli-1 is involved in vessel stabilization by regulating recruitment and/or maintaince of pericytes. We hypothesize that downregulation of Fli-1 is a critical pathogenic event that leads to EC dysfunction concurrent with deregulated collagen production by fibroblasts. Specifically, we hypothesize that Fli-1 is involved in regulating proper interactions between endothelial cells and perivascular cells. Persistent downregulation of Fli-1 in microvascular endothelial cells and/or pericytes leads to detachment of perivascular cells and subsequent EC dysfunction, leading to deterioration of the vessel. To test these hypotheses we propose to use unique genetic mouse models with tissue specific deletion of Fli1 in fibroblasts or/and endothelial cells.
In Aim 1, we will determine the functional consequences of Fli1 reduction in fibroblasts on ECM production and vessel regeneration.
In Aim 2, we will determine the functional consequences of Fli-1 reduction in ECs on skin vasculature and fibroblast activation.
In Aim 3, we will determine the molecular mechanisms involved in regulating Fli-1 function in fibroblasts and ECs.

Public Health Relevance

The pathogenesis of SSc is still poorly understood and there are no effective anti-fibrotic treatments. The proposed studies of the molecular basis of SSc may provide a unifying mechanism for microangiopathy and fibrosis, two main features of this disease. Furthermore, these studies will demonstrate the utility of a unique mouse model for SSc supporting future mechanistic as well as effective translational studies utilizing this model. The new knowledge generated by these studies may ultimately provide a logical target for therapeutic intervention.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-MOSS-C (02))
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Tseng, Hung H
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Boston University
Internal Medicine/Medicine
Schools of Medicine
United States
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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
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
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
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Akamata, Kaname; Asano, Yoshihide; Yamashita, Takashi et al. (2015) Endothelin receptor blockade ameliorates vascular fragility in endothelial cell-specific Fli-1-knockout mice by increasing Fli-1 DNA binding ability. Arthritis Rheumatol 67:1335-44
Kudo, Hideo; Jinnin, Masatoshi; Asano, Yoshihide et al. (2014) Decreased interleukin-20 expression in scleroderma skin contributes to cutaneous fibrosis. Arthritis Rheumatol 66:1636-47
Farina, Antonella; Cirone, Mara; York, Michael et al. (2014) Epstein-Barr virus infection induces aberrant TLR activation pathway and fibroblast-myofibroblast conversion in scleroderma. J Invest Dermatol 134:954-964
van Bon, Lenny; Affandi, Alsya J; Broen, Jasper et al. (2014) Proteome-wide analysis and CXCL4 as a biomarker in systemic sclerosis. N Engl J Med 370:433-43

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