Gokul C. Das Ph.D.
Hepatitis C virus replication and viral pathogenesis; development of antiviral therapy
- Assistant Professor
Baylor College of Medicine - 713-798-3010
- gcdas@bcm.edu
Ph.D.: University of Calcutta, India
Post Docs: Institut de Biologie Moleculaire et Cellulaire du CNRS, Strasbourg, France
National Institutes of Health
Hepatitis C virus (HCV) infection is a global public health problem and is strongly associated with chronic hepatitis, cirrhosis and development of hepatocellular carcinoma (HCC). Since HCC does not occur in all cases of chronic infection and an extended time span of about 20-30 years is required for tumor development, it is not understood whether HCV infection is the cause or the effect in the development of HCC. Our current understanding of the molecular events leading to tumor development and of the nature of the viral and cellular factors involved are very limited.
Chronic viral infection also causes other extrahepatic diseases, such as diabetes type 2 milletus. The incidence of diabetes is about three times more in HCV infected individuals. Epidemiological study indicate that HCV infection itself can cause insulin resistance in chronic infection independent of other liver diseases. This occurs through the disruption of the insulin signaling pathway presumably by the viral proteins.HCV patients with insulin resistance are difficult to treat by conventional interferon and ribavirin therapy.
. It is well accepted that alteration of insulin signaling pathway plays important roles in many cancer types. This is further related to the induction of programmed cell death including both apoptosis and autophagy, the latter being a process important in the maintenance of physiological functions of normal tissues that is not well studied in relation to cancer. Insulin negatively regulates autophagy and a part of autophagic machinery is involved in innate immunity and control host’s response in antiviral therapy. Our central hypothesis is disruption of insulin signaling pathway modulates autophagic response in chronically infected cells as a contributory factor both in HCV induced pathgenesis and in response to interferon based antiviral therapy.
In the absence of a small animal models for HCV replication, we have been using a cellular model that produces HCV continuously in culture mimicking chronic infection and this cell line exhibits insulin resistance by several important criteria. By exploiting this cell culture system and proteomics analysis, our major focus is to understand how HCV infection disrupts insulin signaling pathway and what are the viral and cellular proteins involved in this process. Along this line, we are also interested to understand how autophagy is related to viral pathogenesis and innate immunity controlling host’s response to antiviral therapy. Our study thus will identify the molecular signatures in viral infection and pathogenesis and advance development of better therapeutic strategies.
Selected Publications:
Das GC, Bacsi A, Sreevastava M, Hazra, T. and Boldogh I. (2006) Enhanced expression of Gamma-glutamylcysteine synthetase activity decreases oxidative stress level and cytotoxicity. Mol Carcinog. 45:635-47.
Vertrees RA, Das GC, Popov VL, Cosci AM, Goodwin TJ, Logrono R, Zwischenberger JB, Boor PJ. (2005) Synergistic interaction of hyperthermia and gemcitabine in Lung Cancer. Cancer Biol Ther. 4:1144-1153.
Vertrees RA, Das GC, Coscio AM, Xie J, Zwischenberger JB, Boor PJ. (2005) A mechanism of hyperthermia-induced apoptosis in ras transformed lung cells. Mol Cacinog. 44:111-121.
Bolddogh I, Bhakat K, Das GC, Bocangel D and Mitra S. (2004) Regulation of DNA repair and apoptosis by p53 and its impact on alkylating drug resistance in tumor cells. In: Cancer Discovery and Development: DNA Repair in Cancer Therapy. Eds. Panci LC and Alaoui-Jamali MA. The Human Press INC, Totowa, NJ, 2004.
Boldogh I, Roy G, Lee MS, Hazra T, Bhakat K, Das GC and Mitra S. (2003) DNA double strand break repair: down regulation by oxidative stress. Mol Toxicol. 193:137-152.
Das GC, Gallardo G and Haas C. (2001) Taxol-induced cell cycle arrest and apoptosis: dose-response relationship in cells with different p53 status and under isogenic conditions. Cancer Lett. 165:147-153.
Lee IK, Lee S, Das GC, Poo HR and Lee YI. (2000) Activation of the insulin-like growth factor II transcription by aflatoxin B1-induced p53 mutant 249 is caused by activation of transcriptrion complexes; implications for a gain-of-function during formation of hepatocellular carcinoma. Oncogene 19:3717.
Shivakumar CV and Das GC. (1998) The A enhancer of Polyoma virus: protein-protein interactions for the differential early and late promoter functions under non-replicating conditions. Intervirology 41:103-109.
Shivakumar CV and Das GC. (1996) p53 binding and transactivation of human polyomavirus BK promoter. Oncogene 13:323.