Our laboratory studies kidney development, kidney-specific gene regulation, and polycystic kidney disease. The goal of our research is to understand the transcriptional regulation of kidney development and the molecular pathogenesis of cystic kidney diseases. Our general approach is to use a combination of biochemical and genetic approaches in transgenic, knockout, and conditional knockout mice to identify and characterize the transcription factors that regulate the expression of clinically relevant genes.
One project is studying the role of hepatocyte nuclear factor-1beta (HNF-1beta) in kidney-specific gene regulation, kidney development, and renal cystic diseases. Mutations of HNF-1beta produce renal cysts and diabetes. We have shown that transgenic mice expressing mutant HNF-1beta develop cystic kidneys and renal failure. The mechanism of cyst formation involves down-regulation of the gene responsible for autosomal recessive polycystic kidney disease (PKHD1). Current studies are directed at identifying additional HNF-1beta target genes in the kidney and understanding how HNF-1beta regulates PKHD1 gene transcription.
A second project seeks to understand the molecular pathogenesis of polycystic kidney disease, which is the most common genetic cause of renal failure in humans. These studies are focused on the role of the primary cilium in cell signaling, gene regulation, and planar cell polarity.
RESEARCH INTERESTS
Polycystic kidney disease
Gene regulation
Kidney
Transcription factor
Knockout mice
RECENT PUBLICATIONS
Hiesberger, T., Shao, X., Gourley, E., Reimann, A., Pontoglio, M., and Igarashi, P., "Role of the hepatocyte nuclear factor-1beta (HNF-1beta) C-terminal domain in Pkhd1 (ARPKD) gene transcription and renal cystogenesis" Journal of Biological Chemistry, 280:10578-10586, 2005
Hiesberger T, Gourley E, Erickson A, Koulen P, Ward CJ, Masyuk TV, Larusso NF, Harris PC, Igarashi P, "Proteolytic cleavage and nuclear translocation of fibrocystin is regulated by intracellular Ca2+ and activation of protein kinase C" J Biol Chem, 281:34357-34364, 2006
Pollard PJ, Spencer-Dene B, Shukla D, Howarth K, Nye E, El-Bahrawy M, Deheragoda M, Joannou M, McDonald S, Martin A, Igarashi P, Varsani-Brown S, Rosewell I, Poulsom R, Maxwell P, Stamp GW, Tomlinson IP, "Targeted inactivation of fh1 causes proliferative renal cyst development and activation of the hypoxia pathway" Cancer Cell, 11:311-319, 2007
57. Williams, S.S., Cobo-Stark, P., James, L.R., Somlo, S., and Igarashi, P., "Kidney cysts, pancreatic cysts, and biliary disease in a mouse model of ARPKD" Pediatr Nephrol, 23:733-741, 2008
58. Shibazaki, S., Yu, Z., Nishio, S., Tian, X., Thomson, R.B., Mitobe, M., Louvi, A., Velazquez, H., Ishibe, S., Cantley, L.G., Igarashi, P., and Somlo, S., "Cyst formation and activation of the extracellular regulated kinase pathway after kidney specific inactivation of Pkd1" Hum. Mol. Genet., in press 2008
SIGNIFICANT PUBLICATIONS
Lin, F., Hiesberger, T., Cordes, K., Sinclair, A.M., Goldstein, L.S.B., Somlo, S., Igarashi, P., "Kidney-specific inactivation of the KIF3A subunit of kinesin-II inhibits renal ciliogenesis and produces polycystic kidney disease" Proc. Natl. Acad. Sci. USA, 100:5286-5291, April 2003
Hiesberger, T., Bai, Y., Shao, X., McNally, B.T., Sinclair, A.M., Tian, X., Somlo, S., and Igarashi, P., "Mutation of hepatocyte nuclear factor-1beta inhibits Pkhd1 gene expression and produces renal cysts in mice" Journal of Clinical Investigation, 113:814-825, March 2004
Gresh, L., Fischer, E., Reimann, A., Tanguy, M., Garbay, S., Shao, X., Hiesberger, T., Fiette, L., Igarashi, P., Yaniv, M., and Pontoglio, M., "A transcriptional network in polycystic kidney disease." EMBO Journal, 23:1657?1668, 2004
59. Patel, V., Li, L., Cobo-Stark, P., Shao, X., Somlo, S., Lin, F., and Igarashi, P., "Acute kidney injury and aberrant planar cell polarity induce cyst formation in mice lacking renal cilia" Hum. Mol. Genet., in press 2008
54. Ma, Z., Gong, Y., Patel, V., Karner, C.M., Fischer, E., Hiesberger, T., Carroll, T.J., Pontoglio, M., and Igarashi, P., "Mutations of HNF-1β inhibit epithelial morphogenesis through dysregulation of SOCS-3" Proc. Natl. Acad. Sci. USA, 104:20386-20391, 2007
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