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Zhaoxia Sun, PhD

Associate Professor of Genetics; Co-Director of Graduate Studies, Genetics

Research Summary

We study a tiny cell surface organelle called the cilium. The cilium plays a critical role in animal development and in multiple human diseases. We are particularly interested in two genetic diseases caused by ciliary defects: polycystic kidney disease (PKD) and primary ciliary dyskinesia (PCD). Our ultimate goal is to understand how cilia are built and how cilia mediate cellular function, thus provide insight for rational designing of treatment against ciliopathies, diseases caused by ciliary defects.

Specialized Terms: Cilium; Ciliopathy; Kidney Development; Mouse Genetics; Primary ciliary dyskinesia (PCD); Polycystic Kidney Disease (PKD); Zebrafish Genetics

Extensive Research Description

The cilium is a hair like cell surface organelle that is almost ubiquitously present on vertebrate cells. While motile cilia beat to propel cell movement or fluid flow over the cell surface, immotile cilia function as cellular antennae that detect extracellular signals and couple them to cellular responses. 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. Complementary to the zebrafish system, mouse is a mammalian model suitable for validation of functional conservation and translational research.

Originally founded as the first zebrafish lab in Yale School of Medicine, our research has expanded into mouse and cell culture systems. We are striving to tease 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 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. 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. More recently we demonstrated the role of epithelial-stromal crosstalk in cyst formation and interstitial fibrosis in renal ciliopathies.

In addition, we are studying a motile ciliopathy called primary ciliary dyskinesia (PCD), characterized by chronic pulmonary infection and can progress to respiratory failure if unmanaged. By collaborating with human genetic groups, we contributed to the identification of PIH1D3 as a gene associated with PCD. We discovered the critical role of Ruvbl1/Pontin and Ruvbl2/Reptin in building dynein arms, the macromolecular machine that powers cilia motility, and showed that they co-localize to droplet like cytosolic foci together with the dynein arm assembly factor Lrrc6, and our recent findings point to novel mechanisms for building dynein arms at scale.


Research Interests

Fibrosis; Genetics; Kartagener Syndrome; Kidney; Polycystic Kidney Diseases; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Zebrafish; Ciliopathies

Selected Publications