Our major research effort focuses on identifying the genetic factors involved in the pathogenesis of autosomal recessive polycystic kidney disease (ARPKD). This work has two components: (1) positional cloning efforts to identify disease genes and (2) complex trait analyses to identify candidate modifier genes. As part of the International ARPKD Consortium, our group cloned PKHD1, the major gene involved in human ARPKD. In addition, we have characterized two distinct mouse models, cpk and bpk, in which the disease phenotype closely resembles human ARPKD and identified the genes, Cys1 and Bicc1, disrupted in each model, respectively. Current efforts are centered on characterizing the functional roles of these genes and their protein products in normal development and disease pathogenesis. Using the cpk mouse model, we have identified Kif12, a gene encoding a novel cilia/flagellar kinesin as a candidate genetic modifier of RPKD pathogenesis.

 

In a set of related activities, we have established the P30-funded UAB Recessive Polycystic Kidney Disease Core Center (http://www.rpkdcc.uab.edu/), an interdisciplinary center of excellence in PKD-related research, with specific emphasis on recessive PKD.

 

Our long-term research objectives are to use clinical data and genetic tools developed from both the human and mouse model studies (1) to identify markers for disease progression in human ARPKD, (2) to dissect the disease pathogenesis, and (3) to establish a molecular platform for designing more effective, targeted therapeutic interventions for affected infants and children.

 

Finally, our group is exploring genotype-phenotype correlations in other inherited renal disorders, such as focal and segmental glomerulosclerosis (FSGS).

• Su Bu, Ph.D.,   Postdoctoral Fellow

• George Yang, M.D.,   Postdoctoral Fellow

• Ravindra Boddu,   Graduate Student

• Jacob Watts,   Graduate Student

• John Wehby , M.S.,   Lab Manager/Research Associate

1. Mrug M, Zhou J, Woo Y, Cui X, Szalai AJ, Novak J, Churchill GA, Guay-Woodford LM. Overexpression of innate immue response genes in a model of recessive polycystic kidney diseases.  Kidney Int. 73:63-76, 2008.  PMID: 17960140
2. Grantham JJ, Cook LT, Torres VE, Bost JE, Chapman AB, Harris PC, Guay-Woodford LM, Bae KT. Determinants of renal volume in autosomal-dominant polycystic kidney disease. Kidney Int. 73:108-116, 2008.  PMID: 17960141
3. Garcia-Gonzalez MA, Menezes LF, Piontek KB, Kaimori J, Huso DL, Watnick T, Onuchic LF, Guay-Woodford LM, Germino GG. Genetic interaction studies link autosomal dominant and recessive polycystic kidney in a common pathway. Hum Mol Genet.  16:1940-1950, 2007.  PMID: 17575307
4. Kaimori JY, Nagasawa Y, Menezes LF, Garcia-Gonzalez MA, Deng J, Imai E, Onuchic LF, Guay-Woodford LM, Germino GG. Polyductin undergoes notch-like processing and regulated release from primary cilia. Hum Mol Genet. 16:942-956, 2007. PMID:17470460
5. Guay-Woodford LM. Renal cystic diseases: diverse phenotypes converge on the cilium/centrosome complex. Pediatr Nephrol. 21:1369-76, 2006. PMID: 16823577
6. Siroky BJ, WB Ferguson, AL Fuson, Y Xie, A Fintha, P Komlosi, BK Yoder, EM Schwiebert, LM Guay-Woodford, PD Bell. Loss of primary cilia results in deregulated and unabated apical calcium entry in ARPKD collecting duct cells. Am J Physiol Renal Physiol. 290:F1320-1328, 2006. PMID: 16396941
7. Sharp AM, LM Messiaen, G Page, C Antignac, M-C Gubler, LF Onuchic, S Somlo, GG Germino, and LM Guay-Woodford. Comprehensive genomic analysis for PKHD1 mutations in ARPKD cohorts. J Med Genet 42:336-349, 2005. PMID: 15805161
8. Mrug M, R Li, X Cui, TR Schoeb, GA Churchill, and LM Guay-Woodford. Kinesin 12 is a candidate polycystic kidney disease modifier in the cpk mouse. J Am Soc Nephrol 16:905-916, 2005. PMID: 15728779
9. Li JB, Gerdes JM, Haycraft CJ, Fan Y, Teslovich TM, May-Simera H, Li H, Blacque OE, Li L, Leitch CC, Lewis RA, Green JS, Parfrey PS, Leroux MR, Davidson WS, Beales PL, Guay-Woodford LM, Yoder BK, Stormo GD, Katsanis N, Dutcher SK. Comparative genomics identifies a flagellar and basal body proteome that includes the BBS5 human disease gene. Cell. 117:541-552, 2004. PMID: 15137946
10. Chapman AB, LM Guay-Woodford, JJ Grantham, VE Torres, KT Bae, DA Baumgarten, PJ Kenney, BF King, JF Glockner, LH Wetzel, ME Brummer, WC O'Neill, ML Robbin, WM Bennett, S Klahr, GH Hirschman, PL Kimmel, PA Thompson, JP Miller; Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease cohort. Renal structure in early autosomal-dominant polycystic kidney disease (ADPKD): The Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) cohort. Kidney Int. 64:1035-1045, 2003. PMID: 12911554
11. Guay-Woodford, LM and RA Desmond. Autosomal recessive polycystic kidney disease (ARPKD): the clinical experience in North America. Pediatrics 111:1072-80, 2003. PMID: 12728091
12. Cogswell C, S Price, X Hou, LM Guay-Woodford, L Flaherty, and E Bryda. Mutations in bicaudal C cause severe polycystic kidney disease in the mouse. Mammal Genome 14:242-249, 2003. PMID: 12682776
13. Yoder BK, X Hou, and LM Guay-Woodford. The polycystic kidney disease proteins, polycystin-1, polycystin-2, polaris, and cystin, are co-localized in renal cilia. J Am Soc Nephrol 13:2508-2516, 2002. PMID: 12239239
14. Onuchic LF, Furu L, Nagasawa Y, Hou X, Eggermann T, Ren Z, Bergmann C, Senderek J, Esquivel E, Zeltner R, Rudnik-Schöneborn S, Mrug M, Sweeney W, Avner ED, Zerres K, Guay-Woodford LM, Somlo S, Germino GG. PKHD1, the Polycystic Kidney and Hepatic Disease 1 Gene Encodes a Novel Large Protein Containing Multiple IPT Domains and PbH1 Repeats. Am J Hum Genet 70:1305-1317, 2002. PMID: 11898128
15. Hou X, M Mrug, BK Yoder, EL Lefkowitz, G Kremmidiotis, P D’Eustachio, DR Beier, and LM Guay-Woodford. Cystin, a novel cilia-associated protein, is disrupted in the cpk mouse model of polycystic kidney disease. J Clin Invest 109:533-540, 2002. PMID: 11854326