Polycystic Kidney Diseases (PKD) are the leading cause of end-stage renal failure and are characterized by the development of renal cysts along the entire length of the nephron. They require extensive treatments, such as dialysis and kidney transplantation. Only limited forms of therapy for PKD exist, since the molecular mechanisms underlying the formation of renal cysts are still poorly understood. Over the years, considerable progress has been made in identifying genes mutated in human forms of PKD and in the development of animal models to study the pathogenesis of these detrimental diseases. Besides mouse and rat PKD models, the more primitive pronephric kidney of Xenopus or zebrafish has emerged as an alternative model system to study the molecular mechanisms underlying the epithelial malformations causing PKD. With its fast development and ease of molecular manipulations, the pronephric kidney is an ideal companion system to the study of PKD in humans or mice. In this proposal we will use the mouse metanephros and the amphibian pronephros to study the RNA binding molecule Bicaudal-C. Mice lacking Bicaudal-C protein develop renal cysts as early as embryonic day 15.5. Cyst formation is first detected in the glomerulus, but can later be detected along the entire length of the nephron. Similarly, in Xenopus, loss-of-Bicaudal-C induces a "PKD-like" phenotype in the pronephros. Importantly, the molecular mechanism of Bicaudal-C activity in kidney development and its connection to the genes mutated in human PKD, i.e. Polycystin-1, Polycystin-2 and Polyductin/Fibrocystin is still not understood. This proposal will address these questions. We will test the hypothesis that Bicaudal-C is a translational regulator of genes involved in Polycystic Kidney Disease. It is based on four observations: (1) Bicaudal-C mutant mice have reduced Polycystin-2 mRNA and protein levels before the onset of cyst formation. (2) The regulation of Polycystin-2 is posttranscriptional. (3) Bicaudal-C protein is localized to P-Bodies and has been shown in Drosophila and C. elegans to regulate a selected group of mRNAs at the posttranscriptional level. (4) Many PKD genes have evolutionary conserved miRNA binding sites in their 3'UTR. If successful, this study will provide novel insights to the underlying biological and biochemical pathways leading to the renal cyst formation in PKD. It will integrate one of the least understood PKD genes into the existing paradigms of PKD. As such, it will be directly applicable to future studies of PKD and may provide a new angle for therapeutic interventions.

Public Health Relevance

Polycystic Kidney Diseases are very prevalent, genetic disorders characterized by the formation of fluid-filled cysts in the kidney. This project studies the RNA-binding molecule Bicaudal-C, its molecular mechanism and its connection to those genes mutated in humans forms of Polycystic Kidney Disease. This study will provide new insides into disease progression and novel angles for therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK080745-05
Application #
8529504
Study Section
Special Emphasis Panel (ZRG1-DKUS-K (02))
Program Officer
Rasooly, Rebekah S
Project Start
2009-08-21
Project End
2014-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2013
Total Cost
$322,965
Indirect Cost
$117,255
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Cerqueira, D├ębora M; Tran, Uyen; Romaker, Daniel et al. (2014) Sterol carrier protein 2 regulates proximal tubule size in the Xenopus pronephric kidney by modulating lipid rafts. Dev Biol 394:54-64
Wessely, Oliver; Cerqueira, Debora M; Tran, Uyen et al. (2014) The bigger the better: determining nephron size in kidney. Pediatr Nephrol 29:525-30
Streets, Andrew J; Wessely, Oliver; Peters, Dorien J M et al. (2013) Hyperphosphorylation of polycystin-2 at a critical residue in disease reveals an essential role for polycystin-1-regulated dephosphorylation. Hum Mol Genet 22:1924-39
Zhang, Bo; Romaker, Daniel; Ferrell, Nicholas et al. (2013) Regulation of G-protein signaling via Gnas is required to regulate proximal tubular growth in the Xenopus pronephros. Dev Biol 376:31-42
Escobedo, Noelia; Contreras, Osvaldo; Munoz, Rosana et al. (2013) Syndecan 4 interacts genetically with Vangl2 to regulate neural tube closure and planar cell polarity. Development 140:3008-17
Wessely, Oliver; Tran, Uyen (2011) Xenopus pronephros development--past, present, and future. Pediatr Nephrol 26:1545-51
Zhang, Bo; Tran, Uyen; Wessely, Oliver (2011) Expression of Wnt signaling components during Xenopus pronephros development. PLoS One 6:e26533
Tran, Uyen; Zakin, Lise; Schweickert, Axel et al. (2010) The RNA-binding protein bicaudal C regulates polycystin 2 in the kidney by antagonizing miR-17 activity. Development 137:1107-16