The overall goal of our research is to understand the mechanism of pathologic fibrosis in scleroderma (SSc) focusing on identification and characterization of the key signaling pathways involved in the disease process. There is currently no treatment for SSc and such knowledge is prerequisite for the development of new and effective antifibrotic therapies. While it is well established that activation of the TGF-2 signaling pathway is central to the process of fibrosis in SSc and other fibrotic disorders, the basis for the chronic nature of TGF-2 signaling in fibrosis remains unknown. The possible mechanisms may involve alterations of the components of the TGF-2 signaling pathway resulting in the constitutive pathway activation or alterations of other key signaling molecules that enhance and/or extend the duration of TGF-2 signaling. Our studies during the past funding period uncovered the specific roles for both of these mechanisms in SSc fibrosis. Specifically, we have elucidated a novel profibrotic signaling pathway downstream from the TGF-2 receptor type I (TGF-2RI or ALK 5) that is triggered by an altered ratio of the TGF-2 receptors and leads to activation of Smad1 and ERK1/2 pathways in the absence of activation of the canonical Smad3 pathway. Activation of this signaling cascade results in increased production of connective tissue growth factor (CCN2), a key mediator of the profibrotic response. Our studies have also revealed that the relative abundance of CCN2 plays a critical role in its function as a profibrotic mediator. Whereas moderately elevated levels of CCN2 induce collagen, high expression levels of CCN2 inhibit collagen production and stimulate MMP1. Hitherto, we have established that the Smad1-ERK1/2 pathway is a positive regulator of CCN2 gene expression whereas, activation of Akt inhibits CCN2 production, thus preventing its excessive accumulation. Both, Smad1 and Akt are constitutively elevated in SSc fibroblasts and the balance between these two signaling pathways ultimately determines the expression levels of CCN2. Additional preliminary data have revealed considerable alterations in the components of the mTOR/Akt pathway in SSc fibroblasts and in SSc skin in vivo, consistent with the activation of this pathway in SSc. The proposed studies will test the hypothesis that the TGF-2RI dependent persistent activation of Smad1/ERK1/2 and Akt/mTOR pathways determines the magnitude of CCN2 gene activation and ultimately leads to chronic fibrosis in SSc. To test this hypothesis and to gain additional insights into the fibrogenic role of these signaling pathways we propose the following specific aims:
In Aim 1 we will determine the role of Smad1-Erk1/2-CCN2 axis in SSc fibrosis.
In Aim 2 we will determine the role of the Akt/mTOR pathway in SSc fibrosis.
In Aim 3 we will establish and characterize an in vivo model of SSc based on fibroblast-specific overexpression of TGF-2RI.

Public Health Relevance

The pathogenesis of SSc is still poorly understood and there are no effective anti-fibrotic treatments for SSc or other fibrotic diseases. Proposed analyses of the specific aberrations of the TGF-2 and Akt/mTOR signaling in SSc will provide a better understanding of the mechanisms responsible for chronic activation of these pathways in fibrosis and may lead to development of effective therapeutic strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR044883-13
Application #
7848948
Study Section
Special Emphasis Panel (ZRG1-MOSS-G (02))
Program Officer
Tseng, Hung H
Project Start
1998-01-01
Project End
2013-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
13
Fiscal Year
2010
Total Cost
$353,925
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
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
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
Kartha, Vinay K; Stawski, Lukasz; Han, Rong et al. (2016) PDGFR? Is a Novel Marker of Stromal Activation in Oral Squamous Cell Carcinomas. PLoS One 11:e0154645
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
Stawski, Lukasz; Haines, Paul; Fine, Alan et al. (2014) MMP-12 deficiency attenuates angiotensin II-induced vascular injury, M2 macrophage accumulation, and skin and heart fibrosis. PLoS One 9:e109763
Chan, Edwin S L; Liu, Hailing; Fernandez, Patricia et al. (2013) Adenosine A(2A) receptors promote collagen production by a Fli1- and CTGF-mediated mechanism. Arthritis Res Ther 15:R58
Markiewicz, Margaret; Znoyko, Sergey; Stawski, Lukasz et al. (2013) A role for estrogen receptor-ýý and estrogen receptor-ýý in collagen biosynthesis in mouse skin. J Invest Dermatol 133:120-7
Chrobak, Izabela; Lenna, Stefania; Stawski, Lukasz et al. (2013) Interferon-? promotes vascular remodeling in human microvascular endothelial cells by upregulating endothelin (ET)-1 and transforming growth factor (TGF) ?2. J Cell Physiol 228:1774-83
Lenna, Stefania; Trojanowska, Maria (2012) The role of endoplasmic reticulum stress and the unfolded protein response in fibrosis. Curr Opin Rheumatol 24:663-8

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