Guanging Wu, M.D., Ph.D.
Associate Professor of Medicine, Cell & Developmental Biology
Vanderbilt University Medical Center
421 Preston Building
Nashville, TN 37232-6304
The primary interest of our research program is to unravel the pathogenesis and molecular mechanism of human genetic-related diseases using state-of-the-art molecular technology and well-extended genetic knowledge. Our lab has extensive expertise for manipulating embryonic stem (ES) cells as well as gene targeting and transgenic technologies. Currently, we are working on the field of polycystic kidney diseases, including autosomal dominant polycystic kidney diseases (ADPKD) and autosomal recessive polycystic kidney diseases (ARPKD).
ADPKD is a human genetic disease and results from mutations in two genes, PKD1 and PKD2. ADPKD affects between 1 in 600 and 1 in 1000 live births. The primary clinical manifestation of ADPKD is progressive, bilateral, multiple cyst formation in the kidneys. While ARPKD is one of hereditary renal cystic diseases in infants and children. Although the estimated incidence of ARPKD is widely variable (ranging from 1 in 6,000 to 1 in 55,000 live births), an incidence of 1 in 20,000 has been proposed by clinical geneticists. Based on this number, we estimate the occurrence of heterozygous carriers to be approximately 1 in 70. The clinical spectrum of ARPKD is ectasia of the renal collecting and hepatic biliary ducts, and fibrosis of the liver and kidneys.
ADPKD is heterogenous diseases caused by two genes: PKD1 and PKD2. We have identified PKD2 by positional cloning (Science 1996; 272:1339), and has developed a serial mouse models with inactivation of both ADPKD genes (Cell 1998;93:177, Nature Genetics 2000;24:75, Hum. Mol. Genet. 2002;11:1845). In addition, we have also generated a spectrum of transgenic models for either PKD1 or PKD2 under general promoter and tissue-specific promoters. Our group also identified a positional candidate gene in ARPKD disease interval which have been validated as PKHD1, the ARPKD causal gene, by other groups. Currently, our lab centers on several research interests and goals:
1. Verifying the molecular mechanisms and pathogenesis of ADPKD and ARPKD. We have produced and are generating serial mouse models for ADPKD and ARPKD. These disease models enable us to understand the molecular mechanism of both ADPKD and ARPKD and the function of their causal gene products, polycystins and fibrocystin/polyductin. In addition, we can also generate mouse models with various combinatorial alleles to unrevealing the functional relationship between PKD1, PKD2 and PKHD1.
2. Understanding the factors that modify the expression of the disease phenotype. The identification of genetic modifier(s) for ADPKD is essential for a better understanding of gene-to-gene interactions, predicting the prognosis of ADPKD patients and verifying molecular targets for therapeutic intervention. The preceding evidence suggests that modifier genes may exist for ADPKD. Currently, we are producing at least two mouse congenic strains for either Pkd1 or Pkd2 through the backcross strategy. We will employe these congenic strains (Pkd1 and Pkd2) to identify the modifier(s) by genome quantitative trait locus mapping.
3. Defining other factors involved in cystogenesis of ADPKD and ARPKD. We have produced the mutant Pkd1 and Pkd2 mice carrying a temperature sensitive SV40 large T transgene (ImmortaMouse). The cell lines from different nephron segments derived from these mutant Pkd1, Pkd2 PKHD1 mice can be isolated and generated by current developed techniques. These cell lines will be employed for analyzing and verifying factors whose expression is effected by inactivation of Pkd1, Pkd2 and PKHD1 using a novel mouse cDNA microarray system.
- Fu Y, Kim I, Lian P, Li A, Zhou L, Li C, Liang D, Coffey RJ, Ma J, Zhao P, Zhan Q, Wu G. Loss of Bicc1 impairs tubulomorphogenesis of cultured IMCD cells by disrupting E-cadherin-based cell-cell adhesion.. Eur J Cell Biol., 89428-36, 2010.
- Kim, I, Ding, T, Fu, Y, Li, C, Cui, L, Li, A, Lian, P, Liang, D, Wang, DW, Guo, C, Ma, J, Zhao, P, Coffey, RJ, Zhan, Q, Wu, G Conditional mutation of Pkd2 causes cystogenesis and upregulates beta-catenin. J Am Soc Nephrol, 20(12), 2556-69, 2009.
- Kim, I, Fu, Y, Hui, K, Moeckel, G, Mai, W, Li, C, Liang, D, Zhao, P, Ma, J, Chen, XZ, George, AL, Coffey, RJ, Feng, ZP, Wu, G Fibrocystin/polyductin modulates renal tubular formation by regulating polycystin-2 expression and function. J Am Soc Nephrol, 19(3), 455-68, 2008.
- Kim, I, Li, C, Liang, D, Chen, XZ, Coffy, RJ, Ma, J, Zhao, P, Wu, G Polycystin-2 expression is regulated by a PC2-binding domain in the intracellular portion of fibrocystin. J Biol Chem, 283(46), 31559-66, 2008.
- Liang G, Li Q, Tang Y, Kikuchi T, Wu G, Chen XZ Polycystin-2 is regulated by endoplasmic reticulum-associated degradation.. Hum. Mol. Genet., 171109-1119, 2008.
- Wu Y, Dai XO, Li Q, Chen CX, Mai W, Hussain Z, Long W, Montalbetti N, Li G, Glynne R, Wang S, Cantielle HF, Wu G, Chen XZ Kinesin-2 mediates physical and functional interactions between polycystin-2 and fibrocystin.. Hum. Mol. Genet. , 153280-3290, 2006.
- Li Q, Montalbetti N, Shen PY, Dai XQ, Cheeseman CI, Karpinski E, Wu G, Cantiello HF, Chen XZ Alpha-actinin associates with polycystin-2 and regulates its channel activity. Hum Mol Genet, 141587-603, 2005.
- Mai, W, Chen, D, Ding, T, Kim, I, Park, S, Cho, SY, Chu, JS, Liang, D, Wang, N, Wu, D, Li, S, Zhao, P, Zent, R, Wu, G Inhibition of Pkhd1 impairs tubulomorphogenesis of cultured IMCD cells. Mol Biol Cell, 16(9), 4398-409, 2005.
- Zhang, MZ, Mai, W, Li, C, Cho, SY, Hao, C, Moeckel, G, Zhao, R, Kim, I, Wang, J, Xiong, H, Wang, H, Sato, Y, Wu, Y, Nakanuma, Y, Lilova, M, Pei, Y, Harris, RC, Li, S, Coffey, RJ, Sun, L, Wu, D, Chen, XZ, Breyer, MD, Zhao, ZJ, McKanna, JA, Wu, G PKHD1 protein encoded by the gene for autosomal recessive polycystic kidney disease associates with basal bodies and primary cilia in renal epithelial cells. Proc Natl Acad Sci U S A, 101(8), 2311-6, 2004.
- Li Q, Dai Y, Guo L, Liu Y, Hao C, Wu G, Basora N, Michalak M, Chen XZ Polycystin-2 associates with tropomyosin-1, an actin microfilament component. J Mol Biol. , 325(5), 949-62, 2003 .
- Li Z, Hannigan M, Mo Z, Liu B, Lu W, Wu Y, Smrcka AV, Wu G, Li L, Liu M, Huang CK, Wu D Directional Sensing Requires Gbetagamma-Mediated PAK1 and PIXalpha-Dependent Activation of Cdc42. Cell , 114(2), 215-27, 2003.
- Li Q, Shen PY, Wu G, Chen XZ. Polycystin-2 interacts with troponin I, an angiogenesis inhibitor.. Biochemistry, 42450-7, 2003.
- Xiong H, Chen Y, Yi Y, Tsuchiya K, Moeckel G, Cheung J, Liang D, Tham K, Xu X, Chen XZ, Pei Y, Zhao ZJ, Wu G A Novel Gene Encoding a TIG Multiple Domain Protein Is a Positional Candidate for Autosomal Recessive Polycystic Kidney Disease. Genomics , 8096-104, 2002 .
- Mao J, Maye P, Kogerman P, Tejedor FJ, Toftgard R, Xie W, Wu G, Wu D Regulation of Gli1 transcriptional activity in the nucleus by Dyrk1. J Biol Chem , 277(38), 35156-61, 2002 .
- Xiong, H, Chen, Y, Yi, Y, Tsuchiya, K, Moeckel, G, Cheung, J, Liang, D, Tham, K, Xu, X, Chen, XZ, Pei, Y, Zhao, ZJ, Wu, G A novel gene encoding a TIG multiple domain protein is a positional candidate for autosomal recessive polycystic kidney disease. Genomics, 80(1), 96-104, 2002.
- Wu, G, Tian, X, Nishimura, S, Markowitz, GS, D''Agati, V, Park, JH, Yao, L, Li, L, Geng, L, Zhao, H, Edelmann, W, Somlo, S Trans-heterozygous Pkd1 and Pkd2 mutations modify expression of polycystic kidney disease. Hum Mol Genet, 11(16), 1845-54, 2002.
- Wu G Current advances in molecular genetics of autosomal-dominant polycystic kidney disease. Curr Opin Nephrol Hypertens. , 10(1), 23-31, 2001 .
- Wu G, Markowitz GS, Li L, D'Agati VD, Factor SM, Geng L, Tibara S, Tuchman J, Cai Y, Park JH, van Adelsberg J, Hou H Jr, Kucherlapati R, Edelmann W, Somlo S Cardiac defects and renal failure in mice with targeted mutations in Pkd2. Nat Genet. , 1(24), 75-8, 2000.
- Park JH, Li L, Cai Y, Hayashi T, Dong F, Maeda Y, Rubin C, Somlo S, Wu G Cloning and characterization of the murine pkd2 promoter. Genomics, 66(3), 305-12, 2000.
- Wu G, D'Agati V, Cai Y, Markowitz G, Park JH, Reynolds DM, Maeda Y, Le TC, Hou H Jr, Kucherlapati R, Edelmann W, Somlo S Somatic inactivation of Pkd2 results in polycystic kidney disease. Cell, 93(2), 177-88, 1998.
- Mochizuki T, Wu G, Hayashi T, Xenophontos SL, Veldhuisen B, Saris JJ, Reynolds DM, Cai Y, Gabow PA, Pierides A, Kimberling WJ, Breuning MH, Deltas CC, Peters DJ, Somlo S PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein. Science, 272(5266), 1339-42, 1996.