Maria Trojanowska, PhD

Project 3 PIMaria

Institution: Boston University School of Medicine

Academic Rank: Professor of Medicine

Medical school/Degree:  Warsaw University, M.S./Polish Academy Of Science, Institute of Biochemistry and Biophysics, Warsaw, Poland, Ph.D.

Mailing address: 72 East Concord Street, E-5, Boston, MA 02118

Email: trojanme@bu.edu

Phone: 617.638.4318

Summary of academic interest:  Scleroderma (SSc) is an autoimmune disease characterized by vascular abnormalities, activation of the immune system, and prominent fibrosis of the skin. Our laboratory focuses on the molecular and cellular mechanisms that underlie pathogenic processes responsible for tissue fibrosis and vasculopathy in scleroderma.

1. Fli1 deficiency – a dual role in fibrosis and vasculopathy in SSc:

Transcription factor Fli1 is a key regulator of collagen homeostasis in healthy tissues, which functions as a potent repressor of interstitial collagens and other matrix protein genes in fibroblasts. Importantly, Fli1 is an antagonist of the key profibrotic cytokine, TGFβ. TGFβ abrogates inhibitory effects of Fli1 through a mechanism that involves activation of the c-Abl/PKCδ/PCAF axis. Expression of Fli1 is consistently reduced in the skin of patients with SSc, supporting the notion that its absence may directly contribute to activation of SSc fibroblasts and uncontrolled matrix deposition in SSc skin in vivo.

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Fli1 is also prominently expressed in endothelial cells (ECs) and pericytes in healthy skin, however it is significantly reduced in SSc vessels even in the early stages of the disease (clinically uninvolved skin). Mice with the endothelial-specific deletion of Fli1 gene (Fli1 CKO) display many features of SSc vasculopathy, including hyperpermeability of dermal vessels, improperly organized dermal vascular network, microaneurysm formation, and dilation of capillaries. Furthermore, Fli1 CKO mice display exaggerated remodeling of pulmonary vessels, when challenged with hypoxia. We are actively investigating genetic mouse models with tissue specific deletions of Fli1 to gain the new insights into the mechanisms of vasculopathy and fibrosis in SSc.

2. Abnormal TGF-β signaling in scleroderma:

Our laboratory has a long-standing interest in understanding how TGF-β signaling contributes to fibrosis. While it is well established that activation of the TGF-β signaling pathway is central to the process of fibrosis in scleroderma and other fibrotic disorders, the basis for the chronic nature of TGF-β signaling in fibrosis remains unknown. We become interested in elucidating TGF-β/Smad1 signaling pathway in dermal fibroblasts. We observed that this pathway is constitutively activated in a subset of SSc fibroblasts. Importantly, our studies have revealed that activation of this pathway leads to the enhanced production of the two key profibrotic mediators, CCN2 (connective tissue factor) and Endothelin 1 with important roles in SSc pathogenesis. Blockade of this pathway may be beneficial for patients with SSc.

Members of the laboratory:

Andreea Bujor, MD, Rong Han, PhD, Shizhong Bu, PhD, Izabela Chrobak, PhD, Stefania Lenna, MS, Lukasz Stawski, MS, Heather Cohen, Paul Haines.

Recent publications relevant to the CORT:

Nakerakanti S, Kapanadze B, Yamasaki M, Markiewicz M, and Trojanowska M. Fli1 and Ets1 have distinct roles in the CTGF/CCN2 gene regulation and induction of the profibrotic gene program. J Biol Chem 281:25259-25269, 2006

Pannu J, Nakerakanti S, Smith E, ten Dijke P, and Trojanowska M. TGF-b receptor type I dependent fibrogenic program is mediated via activation of Smad1 and ERK1/2 pathways, J Biol Chem 286:104105-10413, 2007

Asano Y, Czuwara-Ladykowska J, and Trojanowska M. TGF-β regulates DNA binding activity of transcription factor Fli1 by PCAF-dependent acetylation. J Biol Chem, 282:34672-34683, 2007

Pannu J, Asano Y, Nakerakanti S, Smith E, Jablonska S, Blaszczyk M, ten Dijke P, and Trojanowska M. Smad1 pathway is activated in SSc fibroblasts and is targeted by imatinib mesylate, A&R, 58:2528-2537, 2008

Bu S, Kapanadze B, Hsu T, and Trojanowska M. Opposite effects of dihydrosphingosine 1- phosphate and sphingosine 1-phosphate on TGF-β/Smad signaling are mediated through the PTEN/PPM1A dependent pathway, J Biol Chem, 283:19593-19602, 2008.

Asano Y, Markiewicz M, Kubo M, Szalai G, Watson DK, Trojanowska M. Transcription factor Fli1 regulates collagen fibrillogenesis in mouse skin. Mol Cell Biol. 29(2):425-34, 2009.

Asano Y, Trojanowska M. Phosphorylation of Fli1 at threonine 312 by protein kinase C-{delta} promotes its interaction with p300/CREB-binding protein-associated factor and subsequent acetylation in response to transforming growth factor-{beta}. Mol Cell Biol. 29:1882-94, 2009

Asano Y, Stawski L, Hant F, Highland K, Silver R, Szalai G, Watson DK, and Trojanowska M. Endothelial Fli1 deficiency impairs vascular homeostasis – a role in scleroderma vasculopathy. Am J Pathol, 176:1983-1998, 2010

Bu S, Asano Y, Bujor A, Highland K, Hant F, and Trojanowska M. Dihydrosphingosine-1 phosphate has a potent anti-fibrotic effect in Scleroderma fibroblasts via normalization of PTEN levels, A&R, 62:2117, 2010

Trojanowska M. Cellular and molecular aspects of vascular disease in systemic sclerosis. Nature Reviews in Rheumatology. 6:453-460, 2010

Lenna S, Townsend DM, Tan FK, Kapanadze B, Markiewicz M, Trojanowska M, Scorza R. HLA- B35 upregulates Endothelin-1 and downregulates endothelial nitric oxide synthase via endoplasmic reticulum stress response in endothelial cells. J Immunol. 184:4654-61, 2010

Bujor A, Asano Y, Haines P, Lafyatis R, and Trojanowska M. The c-Abl tyrosine kinase controls PKCδ induced Fli1 phosphorylation in human dermal fibroblasts. A&R, 63:1729,2011

Hattori T, Stawski L, Nakerakanti S, and Trojanowska M. Fli1 is a negative regulator of estrogen receptor alpha in dermal fibroblasts. J Invest Dermatol, in press

Markiewicz M, Nakerakanti SS, Kapanadze B, Ghatnekar A, Trojanowska M. Connective tissue growth factor (CTGF/CCN2) mediates angiogenic effect of S1P in human dermal microvascular endothelial cells Microcirculation 18:1, 2011

Morris E, Chrobak I, Bujor A, Hant F, Mummery C, Ten Dijke F, Trojanowska M. Endoglin promotes TGF-β/Smad1 signling in scleroderma fibroblasts. J Cell Phys, in press

Nakerakanti S, Bujor A, and Trojanowska M. CCN2 is required for the activaton of Smad1-Erk1/2 signaling network, PlosOne, 6:e21911, 2011.

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