John Varga, MD Professor Medicine TGF-ß and the Pathogenesis of Fibrosis Curricula: Cell Biology Molecular Biology and Genetics E-mail:   j-varga@northwestern.edu

The long-term goal of projects in my lab is to understand the process of fibrosis (scarring) that results from tissue injury in the lungs, kidney, liver, and in association with autoimmune and inflammatory diseases in multiple organs. A fundamental assumption is that scarring in all of these organs and diverse pathological processes involves similar cellular and molecular mechanisms.

A main objective is to study the role of the pleiotropic cytokine TGF-ß in fibrosis in the development of fibrosis using human material and animal models. The studies focus on the regulation of fibroblast activation in the development of fibrosis. We use a broad-based translational research approach in order to design novel treatment strategies for scleroderma, as well as related fibrotic diseases such as liver cirrhosis, keloid and post-burn hypertrophic scars, and pulmonary fibrosis. Recent studies have focused on the Smad signal transduction pathways, and their interaction with other kinase cascades. Small molecule inhibitors of these pathways are undergoing evaluation in vitro and in vivo. The laboratory studies are closely integrated with the research activities of the Northwestern Scleroderma Center, a major clinical program in Scleroderma, and laboratory research in several other groups at Northwestern, including Hepatology, Pediatric Nephrology, Plastic Surgery and the Cancer Center. 

Research studies focus on the regulation of TGF-ß responses by Smads, a novel family of intracellular signal transducers and tumor suppressors. We use genome-wide screens, mice with targeted gene deletions transcriptional assays, and immunohistology and other morphological analyses to define the role of Smads in fibrosis. We have established that Smads play an essential role in TGF-ß stimulation of cellular fibrotic responses, and the development of pathological fibrosis. We have developed and characterized a novel murine model of scleroderma, which permits more physiological dissection of TGF-ß signaling in vivo in the context of fibrosis. We plan to develop novel types of genetic and biochemical approaches in order to selectively block Smad function in mesenchymal cells, and assess the clinical significance of such blockade in the development of fibrosis using our novel murine model.

Publications:

Ghosh AK, Yuan W, Mori Y, Chen S-J, VARGA J. Antagonistic regulation of Type I collagen gene expression by interferon-g and TGF-ß: Integration at the level of p300/CBP transcriptional co-activators. J Biol Chem. 276:11041-11048, 2001.

Yuan W, VARGA J. Transforming growth factor-ß repression of matrix metalloproteinase-1 in dermal fibroblasts involves smad3.  J Biol Chem. 276:38502-38510, 2001.

Ghosh AK, Bhattacharyya S, Mori Y, Chen SJ, VARGA J. Peroxisome proliferator-activated receptor-g disrupts TGF-ß signaling and profibrotic responses in normal fibroblasts. Arthritis Rheum. 2004; 50:1305-18.

Lakos G, Takagawa S, Wang X-J, DiPietro L, VARGA J. Modulation of bleomycin-induced dermal fibrotic responses in vivo and in vitro in the absence of Smad3. Am J Pathol. 2004;165(1):203-17.

Ghosh A, Bhattacharyya S, VARGA J. The tumor suppressor p53 modulates collagen gene expression and other TGF-ß responses in normal human fibroblasts. J Biol Chem. 2004 Sep 1 [Epub ahead of print]

Mori Y, Ishida W, VARGA J. A novel low molecular weight inhibitor of the ALK5 Type I TGF-ß receptor kinase abrogates profibrotic responses in normal human fibroblasts Arthritis Rheum (in press, 2004).

View Publications by John Varga listed in the National Library of Medicine (PubMed).