Faculty and Staff
Nutritional and Metabolic Doctoral Training Faculty
Robert Schwabe, M.D.
Assistant Professor of Medicine
Digestive and Liver Diseases Columbia University
Defining Signaling Pathways that promote the development of liver fibrosis and liver cancer.
The aim of the Schwabe lab is to understand the regulation of wound healing responses to chronic liver injury with a specific focus on how the activation of hepatic stellate cells promotes liver fibrosis and liver carcinogenesis. We postulate that many pathways that promote beneficial wound healing responses in the short term, promote the development of fibrosis and cancer in the long term.
1. Inflammation and wound healing: Inflammation is a characteristic feature of chronic liver injury. Despite the overwhelming association between inflammation and wound healing in virtually all stages of liver injury, the causal contribution of inflammation towards the development of liver fibrosis and cancer is not well understood. Our laboratory hypothesizes that there is an increased exposure of the liver to inflammatory mediators released from the intestinal microbiota, and that these products trigger inflammatory signaling cascades that promote the development of liver cancer and fibrosis. The laboratory is focusing on the involvement of the gut microbiota, Toll-like receptors and their downstream mediators such as NF-kB and JNK in the promotion of fibrogenesis and carcinogenesis.
2. Characterization of stellate cell activation: Following liver injury, stellate cells undergo a phenotypic change to transform from vitamin A storing, lipid droplet-containing cells to myofibroblast-like cells. However, this transformation has been largely studied in cell culture, and the role of stellate cells as predominant source of liver myofibroblasts in the fibrotic liver has not been established without absolute certainty. Using a novel "snapshot" technology that allows to purify stellate cells from the fibrotic liver without any plating or other artifacts, the Schwabe lab is characterizing in detail cellular programs that regulate stellate cell activation, and is modulating these pathways in a stellate cell-specific manner to determine the relevance of key pathway in vivo.
3. Endocannabinoids and liver disease: Endocannabinoids are bioactive lipids that regulate a wide range of biological functions such as food intake, metabolism, inflammation, cell proliferation and apoptosis. The Schwabe lab is interested how endocannbinoids affect wound healing responses in different cellular compartments of the liver. Using genetic approaches, the lab is studying how cell-specific inactivation of cannabinoid receptors or increases in endocannabinoid levels affect wound healing response to chronic injury.
4. Generation of novel mouse models of liver fibrosis, inflammation and cancer: The Schwabe lab is using Bac recombineering technology to generate a number of novel genetic models of liver fibrosis, inflammation and hepatocellular cancer. The approaches includes the (i) generation of novel Cre transgenic lines, (ii) floxing of target genes and (iii) the generation of "knock-in" mice with point mutations in specific pathways.
1. Kluwe J, Pradere JP, Gwak GY, Mencin A, De Minicis S, Osterreicher CH, Colmenero J, Bataller R, Schwabe RF (2010) Modulation of hepatic fibrosis by c-Jun-N-terminal kinase inhibition. Gastroenterology 138:347-59
2. Seki E, De Minicis S, Gwak GY, Kluwe J, Inokuchi S, Bursill CA, Llovet JM, Brenner DA, Schwabe RF. (2009) CCR1 and CCR5 promote hepatic fibrosis in mice. J Clin Invest 119:1858-70
3. Kluwe J, Mencin A, Schwabe RF.Toll-like receptors, wound healing, and carcinogenesis. J Mol Med 87:25-38
4. Seki E, De Minicis S, Osterreicher CH, Kluwe J, Osawa Y, Brenner DA, Schwabe RF (2007) TLR4 enhances TGF-beta signaling and hepatic fibrosis. Nat Med 13:1324-32
5. De Minicis S, Seki E, Uchinami H, Kluwe J, Zhang Y, Brenner DA, Schwabe RF. (2007) Gene expression profiles/ during hepatic stellate cell activation in culture and in vivo. Gastroenterology 32:2601-4