Polycystic kidney disease is a complex disorder which can result from a variety of gene mutations as well as from environmental insults. Developmental or cellular defects in epithelia caused by cystic mutations are often obscured by compensatory tissue responses, making it difficult to define the primary cause of cystic disease. Despite recent advances in cloning the genes responsible for the majority of polycystic kidney disease (PKD1, PKD2), the function of these genes in normal epithelia remains unknown. The goal of this proposal is to take advantage of the zebrafish as a genetic and developmental system to 1) explore the primary defects in the pronephros caused by cystic mutations in the absence of glomerular filtration, 2) clone and further characterize the zebrafish PKD1 homolog, 3) using a candidate gene approach screen for mutations in zfPKD1 in an existing set of pronephric cyst mutants, and 4) explore the potentially dominant-negative or constitutively active function and of the C-terminal cytoplasmic tail of PKD1 by expressing it in vivo in the context of zebrafish development. This study will identify initial defects associated with cystic mutations and in so doing, help focus the development of therapies on the primary causes of cystic disease. In addition, we will identify cellular and tissue responses which may modify the rate of disease progression or age of onset. The ability to study the PKD1 gene in a system which lends itself to genetic linkage studies, direct observation of development, and embryonic manipulation makes possible an analysis of the role of PKD1 in early development and the onset of cyst formation, determination of cell-autonomous or non cell-autonomous functions of PKD1, and the identification of evolutionarily conserved and functionally important domains of PKD1. It is our hope that the availability of a simple and accessible cystic disease model will help identify novel targets for therapeutic interventions and speed the development treatments for polycystic kidney disease.
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