We study the function of a tiny and almost ubiquitous cell surface organelle called the cilium in development, homeostasis and disease. 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 modulate cellular responses. Cilia dysgenesis and dysfunction have been linked to a growing list of human diseases ranging from polycystic kidney disease (PKD), primary ciliary dyskinesia (PCD), 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. We are particularly interested in two genetic diseases caused by ciliary defects: PKD and PCD. Our ultimate goal is to understand how cilia are built and how cilia mediate cellular functions, thus provide insight for rational designing of treatment against ciliopathies. Toward this goal, we use a multi-disciplinary approach that utilizes zebrafish, mouse and cultured cells as model systems and a variety of methods including imaging, sc-RNA seq, proteomic analysis and chemical genetic screens.
Function of cilia in PKD and renal fibrosis:
Left: Cysts lined by mutant epithelial cells in red and activated myofibroblasts in green, highlighting communications between different cell types.
Drug-gene and drug-drug interaction
Identifying drug-gene and drug-drug interactions is critical for more personalized and effective management of human diseases. Zebrafish is uniquely positioned for systematic evaluation of whole body responses. It is a vertebrate system amenable to both genetic and chemical screens. In our previous study, we identified HDAC inhibitors as suppressors of PKD phenotypes in zebrafish and validated the results in mouse. We are currently expanding our screen.
PCD and the challenge of building a macromolecular machine
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 human. Despite intensive research in the past two decades, the precise molecular mechanism underlying PKD pathogenesis remains elusive. Our past studies have provided strong evidence for the critical role of the cilium in PKD pathogenesis and suggested HDAC inhibitors as chemical suppressors of PKD. Our current questions include molecular and cellular functions of cilia in epithelial cells during development and injury, the role of cilia in interstitial cells and cross-talks between different cell types.
PCD is a progressive lung disease characterized by mucus impaction and recurrent sinopulmonary infections, due to impaired mucociliary clearance, normally driven by motile cilia through the force generated by dynein arms. A fundamental challenge is how these macromolecular machines are accurately and efficiently constructed within the crowded cytosol. We discovered the critical role of Ruvbl1/Pontin and Ruvbl2/Reptin in dynein arm assembly and showed that they co-localize to droplet like cytosolic foci together with the dynein arm assembly factor Lrrc6. We are currently researching how dynein arm assembly factors facilitate the building of dynein arms.
Left: cilia motility defects in zebrafish. Middle: beating cilia in zebrafish nose. Right: Foci of dynein arm assembly factors in green. Cilia in red.