PKD (polycystic kidney disease) is characterized by the formation of multiple kidney cysts that are thought to result from over-proliferation of renal epithelial cells. PKD affects more than 600,000 Americans and half of the patients will progress into end stage renal disease by the age of 60. Presently, no cure is available for this devastating illness. Recent progresses in PKD research suggest that in vertebrates, the cilium, protruding from apical surface of epithelial cells into tube lumen, may act as a sensor for environmental antiproliferative signals. Defects in cilia formation and function can therefore lead to cell over-proliferation and eventual cyst formation. Presently, the best understood aspect of cilia assembly is IFT (intraflagellar transport), microtubule based motility essential for transporting cargoes for cilia assembly. However, how this motility is regulated is poorly understood. This project focuses on seahorse, a cystic kidney mutant we isolated in a genetic screen in zebrafish along with three IFT genes, seahorse mutant show almost identical phenotypes as IFT mutants, indicating that Seahorse protein may be involved in the same pathway as IFT proteins. Interesting, seahorse encodes a highly conserved novel non-IFT protein. In addition, Seahorse protein contains leucine-rich repeats, suggesting that it may be involved in multi-protein complexes. In this project, we will start by characterizing seahorse gene and gene product in detail with in situ, immuno-staining and eGFP tagging.
In Aim 2, we will analyze the cellular basis of seahorse phenotype by examining cell proliferation, apoptosis and cilia formation in seahorse mutants.
In Aim 3, we will dissect the function seahorse first by testing its interaction with IFT genes. We will then use yeast two-hybrid screen and tandem affinity purification to identify binding partners of Seahorse. Finally, in Aim 4, we will collaborate with Somlo lab to test whether the function of seahorse is conserved in mammalian cells. Together, these experiments will shed light on the function of seahorse, a non-IFT gene, in cilia assembly and cyst formation.
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