Dr. NAMITA ROY-CHOWDHURY
The overall goal of my laboratory is to study the liver-based inherited metabolic diseases, mainly, inherited disorders of Bilirubin Glucuronidation and Primary Hyperoxaluria type 1. To understand these diseases we determine the mutations in the genes and structure-function relationship. We also developing methods for correction of these diseases by gene therapy, introducing functional genes by different methods and by liver cell transplantation. As normal liver cells are not easily available and to avoid immune suppression, we collect skin fibroblasts of the patients and reprogram these to induced pluripotent stem cells, differentiate them to hepatocytes and transplant these cells to different animal models to test their efficacy.
I. Inherited Disorders of Bilirubin Glucuronidation. GT1A1 is a member of UDP-glucuronosyltransferases (UGT) family of enzymes, which is concentrated in the hepatic endoplasmic reticulum (ER). UGT1A1 mediates the glucuronidation of bilirubin and estrogens. UGT1A1-mediated glucuronidation is required for excretion of bilirubin in bile. We showed that the genetic lesions in any one of the five exons encoding UGT1A1 can abolish or reduce bilirubin glucuronidation, causing potentially lethal Crigler-Najjar syndrome type I (CN-I), or it’s less severe variant, Crigler-Najjar syndrome type II (CN-II). We also showed that Gilbert syndrome, a milder form of inherited hyperbilirubinemia, is caused by a promoter variation. We have been studying the regulation of UGT1A1 gene expression. Our objective is to develop novel therapies (gene and cell-based therapies) to cure this disease, using the jaundiced Gunn rat model of CN-1.
II. Primary Hyperoxaluria Type 1 (PH1). PH1 is an autosomal recessive disease caused by mutations in the alanine:glyoxylate aminotransferase gene (AGXT). In humans, insufficient AGXT activity in liver peroxisomes leads to increased oxalate production that causes calcium oxalate stones in the kidney and then in blood, heart, bones, etc. It is a lethal disease unless combined liver and kidney transplantation is performed. We have developed a mouse model of PH1. Our plan is to cure this disease by (a) gene therapy (b) transplantation of adult primary hepatocytes or (c) hepatocytes derived from human embryonic (hESC) or induced pluripotent stem cell (iPSC). For the latter, fibroblasts from the skin of normal volunteers or patients with PH1 are used to generate iPS. Initially we used viral vectors to generate induced pluripotent stem cells. Our current focus is to use non-integrating factors to generate iPS cells.
Roy-Chowdhury J, Locker J, Roy-Chowdhury N. Nuclear Receptors orchestrate detoxification pathways. Developmental Cell 4:1-2, 2003.
Ghosh SS, Lu Y, Lee SW, Wang X, Guha C, Roy-Chowdhury J, Roy-Chowdhury N. Role of cysteine residues in the function of human uridinediphosphoglucuronate glucuronosyltransferases-1 (UGT1A1). Biochem J 392:685-692, 2005.
Roy-Chowdhury N, Wang X, Roy-Chowdhury J. Bile Pigment Metabolism and Its Disorders. Principles and Practice of Medical Genetics, Fifth Edition, Rimoin DL, Connor JM, Pyeritz RE, Korf BR, editors. Churchill Livingstone, London, 2006.
Salido E, Li XM, Lu Y, Wang X, Santana A, Roy-Chowdhury N, Torres A, Shapiro L, Roy-Chowdhury J. Alanine-glyoxylate aminotransferase deficient mice, a model for primary hyperoxaluria that responds to adenoviral gene transfer. Proc Natl Acad Sci USA 103:18249-18254, 2006.
Kawashita Y, Guha C, Moitra R, Wang X, Fox I, Roy-Chowdhury J and Roy-Chowdhury N. Hepatic repopulation with stably transduced conditionally immortalized hepatocytes in the Gunn rat. J Hepatol 49:99-106, 2008.
Jiang J, Salido EC, Guha C, Wang X, Moitra R, Liu L, Roy-Chowdhury J and Roy-Chowdhury N. Correction of Hyperoxaluria by liver repopulation with hepatocytes in a mouse model of primary hyperoxaluria type -1. Transplantation 85:1253-1260, 2008.
Roy Chowdhury N, Roy Chowdhury J. Disorders of bilirubin metabolism. In: The Liver: Biology and Pathobiology, 4th Edition, Arias, IM, Editor-in-Chief. Wiley-Blackwell, Oxford, UK, 2009, 251-256.
Roy-Chowdhury N, Roy-Chowdhury J. Liver physiology and energy metabolism. In: Sleisenger and Fordtran’s Gastrointestinal and Liver Disease, 9th Edition.Feldman M, Friedman LS, Brandt LJ, editors. Saunders-Elsevier, Philadelphia, 2010, pp. 1207-1226.
Ding J, Yannam GR, Roy-Chowdhury N, Hidvegi T, Basma H, Rennard SI, Wong RJ, Avsar Y, Guha C, Perlmutter DH, Fox IJ, Roy-Chowdhury J. Spontaneous hepatic repopulation in transgenic mice expressing mutant human alpha1- antitrypsin by wild-type donor hepatocytes. J Clin Invest 121:1930-1934, 2011.
Zhou H, Dong X, Kabarriti R, Chen Y, Avsar A, Wang X, Ding J, Liu L, Fox IJ, Roy-Chowdhury J, Roy-Chowdhury N, Guha C. Single liver lobe repopulation with wildtype hepatocytes using regional hepatic irradiation cures jaundice in Gunn rats. PLoS One 7:e46775, 2012.
Sauer V, Roy-Chowdhury N, Guha C, Roy-Chowdhury J. Induced pluripotent stem cells as a source of hepatocytes. Curr Pathobiol Rep 2:11–20, 2014.
Chen Y, Li Y, Wang X, Zhang W, Sauer V, Chang C-J, Han B, Tchaikovskya T, Avsar Y, Tafaleng EN, Sanal MG, Tar K, Polgar Z, Strom S, Bouhassira EE, Guha C, Fox IJ, Roy-Chowdhury J, Roy-Chowdhury N. Amelioration of hyperbilirubinemia in Gunn rats after transplantation of human induced pluripotent stem cell-derived hepatocytes. Stem Cell Reports 5:22-30, 2015.
Sauer V, Tchaikovskaya T, Wang X, Li Y, Zhang W Tar K, Polgar Z, Ding J, Guha C, Fox IJ, Roy-Chowdhury N, Roy-Chowdhury J. Human urinary epithelial cells as a source of engraftable hepatocyte-like cells using stem cell technology. Cell Transplant 2016 Jun 9 [Epub ahead of print].
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