Zhaoxia Sun PhD

Associate Professor of Genetics

Research Interests

Zebrafish genetics; Cilium; Kidney development; Polycystic kidney disease (PKD); Ciliopathy

Current Projects

Research Summary

We use zebrafish to study polycystic kidney disease (PKD) and other diseases caused by defects in a cell surface organelle called cilium. PKD is a common human genetic disease with severe medical consequences. Currently no directed treatment is available for this disease. Our ultimate goal is to understand cilia-mediated signaling and its role in the etiology of PKD, thus provide insight for rational designing of treatment against this disease and other ciliopathies.

Extensive Research Description

The cilium is a hair like cell surface organelle that is almost ubiquitously present on vertebrate cells. It is believed to function as an antenna for the cell to detect and transduce signals. Not surprisingly, in the past decade, there is an increasing appreciation for the vital role played by this tiny organelle in diverse developmental processes and homeostasis in vertebrates. Consistently, cilia dysgenesis and dysfunction have been linked to a growing list of human diseases ranging from polycystic kidney disease (PKD), cancer, to mental retardation and obesity, collectively referred to as ciliopathies. However, the cilium is also one of the few organelles whose physiology and function remain to be fully interrogated. Despite the amazing structural conservation of this organelle from green algae to human, the function of the cilium has diverged significantly between vertebrates and traditional invertebrate model organisms, including Drosophila and C. elegans.

In contrast to fly and worm, zebrafish shows significant functional conservation of cilia-mediated signaling with mammals. Combined with its amenability to large-scale chemical and genetic screens, the accessibility of cilia in multiple organs and the collection of cilia mutants already available, this feature of zebrafish makes it uniquely positioned as a model system for studying cilia and ciliopathy.

Using a variety of approaches in zebrafish, we are teasing out the mechanisms that govern cilia biogenesis, motility and size and the role of cilia in development and diseases. One disease of particular interest is polycystic kidney disease (PKD). PKD is characterized by the formation of multiple kidney cysts thought to result from over-proliferation of renal epithelial cells. Understanding PKD is of profound medical importance. Striking one in 1000 live births, autosomal dominant form of PKD (ADPKD) is among the most common monogenetic disorders in humans. Aside from kidney transplantation, no directed treatment is available for this disease. Our studies have provided strong evidence for the critical role of the cilium in PKD pathogenesis and suggested HDAC inhibitors as promising candidate drugs for treating PKD. We are expanding our research into the role of cilia in other diseases and are also developing novel tools for studying PKD and cilia in zebrafish.

Selected Publications

  • N. Kishimot, Y. Cao, A. Park and Z. Sun. (2008). Cystic kidney gene seahorse regulates cilia mediated processes and Wnt pathways. Developmental Cell 14:954-961.
  • DiBella, Alice Park and Z. Sun. 2009. Zebrafish Tsc1 reveals functional interactions between the cilium and the Tor pathway. Human Molecular Genetics 18:595-606.
  • N. A. Duldulao, S. Lee and Z.Sun. 2009. Cilia localization is essential for in vivo functions of the Joubert syndrome protein Arl13b/Scorpion. Development 136:4033-4042
  • Ying Cao, Nicole Semanchik, Seung-Hyun Lee, Stefan Somlo, Paolo Emilio Barbano, Ronald Coifman and Zhaoxia Sun. 2009. Chemical modifier screen identifies HDAC inhibitors as suppressors of PKD models. Proc Natl Acad Sci U S A. 106:21819-24.
  • N. E. Hellman, Y. Liu, E. Merkel, C. Austin, S. Corre, D. R. Beier, Z. Sun, N. Sharma, B. K. Yoder, and I. A. Drummond. 2010. foxj1a regulates cilia function in response to injury and epithelial stretch. Proc Natl Acad Sci U S A. 107:18499-504.
  • 6. Y. Cao, A. Park and Z. Sun. 2010. Intraflagella transport proteins are essential for cilia formation and for planar cell polarity. J. Am. Soc. Nephrol. 21:1326-1333.
  • J. Li and Z. Sun. 2011. Qilin Is Essential for Cilia Assembly and Normal Kidney Development in Zebrafish Qilin Is Essential for Cilia Assembly and Normal Kidney Development in Zebrafish. PLoS ONE 6 (11): e27365.
  • B. D. Engel BD, H. Ishikawa, J. L. Feldman, C. W. Wilson, P. T. Chuang, J. Snedecor, J. Williams, Z. Sun, M. F. Marshall. 2011. A cell-based screen for inhibitors of flagella-driven motility in Chlamydomonas reveals a novel modulator of ciliary length and retrograde actin flow. Cytoskeleton 68:188-203.
  • S. Yuan, J. Li, D. R. Diener, M. A. Choma, J. L. Rosenbaum and Z. Sun. 2012. Torc1 signaling modulates cilia size and function through protein synthesis regulation. Proc Natl Acad Sci U S A. 109:2021- [cover] PMC3277533
  • D. Merrick, H. Chapin, J. E. Baggs, Z. Yu, S. Somlo, Z. Sun, J. B. Hogenesch, M. J. Caplan. 2012. The ?-secretase cleavage product of polycystin-1 regulates TCF and CHOP-mediated transcriptional activation through a p300-dependent mechanism. Dev Cell. 17:197-210. PMC3264829

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