UDP-glucuronosyltransferases (UDPGTs) are a group of glycoprotein enzymes concentrated in the endoplasmic reticulum of liver cells, which are essential for the detoxification of internal metabolites and foreign substances, e.g. drugs, carcinogens and environmental toxins. UDPGTs exist as several isoforms; inherited defects of specific forms of UDPGT result in life-long jaundice in man and mutant (Gunn) rats. In preliminary studies we have shown that Gunn rats have approximately normal amounts of two functionally defective UDPGT isoforms. However, the biochemical basis of functional heterogeneity and inherited functional disorders of UDPGTs is not known. The purpose of the proposed project is to determine the possible role of glycosylation and other types of co-translational and post- translational changes in the generation of functional heterogeneity and inherited functional defects of UDPGTs. We plan to develop monoclonal and polyclonal antibodies that are specific for individual UDPGT isoforms and to use these to study the expression of UDPGT genes in inbred normal rats and congeneic Gunn rats. Precursors of individual UDPGT isoforms will be identified by cell-free translation of liver mRNA from normal rats; these precursors will be compared with those derived by translation of Gunn rat liver mRNA. Biosynthetic steps of synthesis of UDPGT precursors and processing of their protein and carbohydrate components will be studied by metabolic labeling of hepatocytes isolated from livers of Gunn rats and congeneic normal rats. Since UDPGTs are integral endoplasmic reticulum proteins, in addition to elucidation of the biochemical basis of inherited disorders of this essential enzyme system, these studies may help us understand the mechanism of assembly of liver endoplasmic reticulum proteins in general.
| Yamanouchi, Kosho; Zhou, Hongchao; Roy-Chowdhury, Namita et al. (2009) Hepatic irradiation augments engraftment of donor cells following hepatocyte transplantation. Hepatology 49:258-67 |
| Wang, Xia; Sarkar, Debi P; Mani, Prashant et al. (2009) Long-term reduction of jaundice in Gunn rats by nonviral liver-targeted delivery of Sleeping Beauty transposon. Hepatology 50:815-24 |
| Wang, Xia; Mani, Prashant; Sarkar, Debi P et al. (2009) Ex vivo gene transfer into hepatocytes. Methods Mol Biol 481:117-40 |
| Jiang, Jinlan; Salido, Eduardo C; Guha, Chandan et al. (2008) Correction of hyperoxaluria by liver repopulation with hepatocytes in a mouse model of primary hyperoxaluria type-1. Transplantation 85:1253-60 |
| Kawashita, Yujo; Guha, Chandan; Moitra, Rituparna et al. (2008) Hepatic repopulation with stably transduced conditionally immortalized hepatocytes in the Gunn rat. J Hepatol 49:99-106 |
| Ghosh, Siddhartha S; Lu, Yang; Lee, Sung W et al. (2005) Role of cysteine residues in the function of human UDP glucuronosyltransferase isoform 1A1 (UGT1A1). Biochem J 392:685-92 |
| Guha, Chandan; Lee, Sung-W; Chowdhury, Namita Roy et al. (2005) Cell culture models and animal models of viral hepatitis. Part II: hepatitis C. Lab Anim (NY) 34:39-47 |
| Guha, Chandan; Mohan, Sankar; Roy-Chowdhury, Namita et al. (2004) Cell culture and animal models of viral hepatitis. Part I: hepatitis B. Lab Anim (NY) 33:37-46 |
| Lee, Sung-W; Wang, Xia; Chowdhury, Namita Roy et al. (2004) Hepatocyte transplantation: state of the art and strategies for overcoming existing hurdles. Ann Hepatol 3:48-53 |
| Guha, Chandan; Shah, Shalin J; Ghosh, Siddhartha S et al. (2003) Molecular therapies for viral hepatitis. BioDrugs 17:81-91 |
Showing the most recent 10 out of 79 publications
