Principal Investigator
Goldyne Savad Institute of Gene Therapy
E-mail: goldenberg@hadassah.org.il
Phone: 972-2-677-8108
Fax: 972-2-643-0982
Affiliation
Hadassah-Hebrew University Medical Center, Jerusalem, Israel
Education
1975 – 1980 M.S. Major: Applied Mathematics. Department of the Applied Mathematics, Moscow Technology Institute of Transport, Moscow, USSR. M.S. thesis: “The database management system on minicomputer for collections of microorganisms”.
1984 – 1987 Ph.D. Post-graduate course of the Institute for genetics and selection of industrial microorganisms (“VNIIGenetica”), Moscow, USSR. Ph.D. thesis: “The host genetic control of the lysis-lysogeny decision of lambdoid phages”.
1990 – 1994 Post-doctorate course of the Hebrew University, Jerusalem, Israel.
Research interests
Molecular mechanisms of liver carcinogenesis and hepatitis C virus pathogenesis. Mouse models of liver carcinogenesis, including transgenic mice expressing HCV proteins. Application of gene expression profiling to study mechanisms of hepatocarcinogenesis.
Selected recent publications
Klopstock N, Katzenellenbogen M, Pappo O, Sklair-Levy M, Olam D, Mizrahi L, Potikha T, Galun E, Goldenberg D. 2009. HCV tumor promoting effect is dependent on host genetic background. PLoS ONE. 4(4):e5025.
Katzenellenbogen M, Mizrahi L, Pappo O, Klopstock N, Olam D, Jacob-Hirsch J, Amariglio N, Rechavi G, Domany E, Galun E, Goldenberg D. 2007. Molecular mechanisms of liver carcinogenesis in the mdr2-knockout mice. Mol Cancer Res. 5(11):1159-70.
Katzenellenbogen M, Mizrahi L, Pappo O, Klopstock N, Olam D, Barash H, Domany E, Galun E, Goldenberg D. 2007. Molecular mechanisms of the chemopreventive effect on hepatocellular carcinoma development in Mdr2 knockout mice. Mol Cancer Ther 6(4):1283-91.
Klopstock N, Levy C, Olam D, Galun E, Goldenberg D. 2007. Testing transgenic regulatory elements through live mouse imaging. FEBS Lett. 581(21):3986-90.
Katzenellenbogen M, Pappo O, Barash H, Klopstock N, Mizrahi L, Olam D, Jacob-Hirsch J, Amariglio N, Rechavi G, Mitchell LA, Kohen R, Domany E, Galun E, Goldenberg D. 2006. Multiple adaptive mechanisms to chronic liver disease revealed at early stages of liver carcinogenesis in the Mdr2-knockout mice. Cancer Res 66(8):4001-10.
Ben-Dor I, Itsykson P, Goldenberg D, Galun E, Reubinoff BE. 2006. Lentiviral vectors harboring a dual-gene system allow high and homogeneous transgene expression in selected polyclonal human embryonic stem cells. Mol Ther 14(2):255-67.
Goldenberg D, Ayesh S, Schneider T, Pappo O, Jurim O, Eid A, Fellig Y, Dadon T, Ariel I, de Groot N, Hochberg A, Galun E. 2002. Analysis of differentially expressed genes in hepatocellular carcinoma using cDNA arrays. Molecular Carcinogenesis 33:113-124.
Goldenberg D, Mador N, Panet A, Steiner I. 1998. Tissue-specific distribution of the herpes simplex virus type 1 latency-associated transcripts on polyribosomes during latent infection. J NeuroVirol 4:426-432.
Mador N, Goldenberg D, Cohen O, Panet A, Steiner I. 1998. Herpes simplex virus type 1 latency-associated transcripts suppress viral replication and reduce immediate early genes mRNA levels in a neuronal cell line. J Virol 72: 5067-5075.
Goldenberg D, Mador N, Ball MJ, Panet A, Steiner I. 1997. The abundant latency-associated transcripts of herpes simplex virus type 1 are bound to polyribosomes in cultured neuronal cells and during latent infection in mouse trigeminal ganglia. J Virol 71:2897-2904.
Goldenberg D, Azar I, Oppenheim AB, Brandi A, Pon CL, Gualerzi CO. 1997. Role of Escherichia coli cspA promoter sequences and adaptation of translational apparatus in the cold shock response. Mol Gen Genet 256:282-290.
Research group
Hecht, Naama, M.Sc. Phone: 677-8781
Katzenellenbogen, Mark, M.Sc. Phone: 677-8783
Potikha, Tamara, Ph.D. Phone: 677-8782
Mizrahi, Lina, M.Sc. Phone: 677-8781/8752
Olam, Devorah, B.Sc. Phone: 677-8947/8781
RESEARCH SUMMARY
Investigation of molecular mechanisms of
hepatocarcinogenesis on mouse models
Hepatocarcinogenesis in mice and humans have many common features, and various mouse models of hepatocellular carcinoma (HCC) have been productively used in studies uncovering the molecular mechanisms of liver carcinogenesis. As a basic mouse HCC model, we use the Mdr2-knockout mice, which lack the Mdr2 P-glycoprotein responsible for the phosphatidylcholine transport across the canalicular membrane. The absence of phospholipids from bile leads to portal inflammation and slowly developing inflammation-associated HCC that mimics in this regard the human disease.
In our work, we use both commercial and our own arrays in order to uncover genes differentially expressed at different stages of HCC development and upon application of different chemopreventive agents. We then compare the results of gene expression profiling with histological and immunohistochemical characterization of the liver samples in order to reveal the gene regulatory pathways that are affected at different stages of HCC development in this model. Functional knockdown of specific regulatory genes in human HCC cell lines or murine HCC models helps confirm the role of these genes in hepatocarcinogenesis.
In parallel we study the effect of HCV proteins on HCC development in mice. We crossed the HCV-Tg mice that express the whole HCV polyprotein, but do not produce HCC, with the Mdr2-knockout mice. Our preliminary results demonstrate that HCV proteins work as cancer accelerators by speeding up the process of HCC development. Gene expression profiling analysis of tumorous and non-tumorous liver tissues of these mice is undertaken now in order to understand the role of HCV proteins in liver carcinogenesis.
These studies should help to reveal the regulatory pathways that are involved in the initiation and progression of inflammation-associated and HCV-associated HCC.
Key Words: Hepatocellular Carcinoma, Hepatitis C Virus, Mouse Model, Gene Expression