The long-term goals of our laboratories are to understand the biological functions of polycystin proteins (PC1 and PC2) encoded by autosomal dominant polycystic kidney disease (ADPKD) genes PKD1 and PKD2, and to determine the pathogenic pathways when they are mutated. By so doing, we seek to establish a firm mechanistic understanding of the ADPKD pathogenesis, which can be used to guide the rational development of therapies. A great obstacle to the development of effective ADPKD therapies has been the lack of a precise understanding of polycystins? key biological function and how its malfunction initiates and drives the disease process. We have most recently discovered that the complex formed by PC1 and PC2 (PC1/PC2), with both of proteins lining the channel pore, functions as a calcium-permeable ion channel, in contrast to the homomeric PC2 channel which primarily conducts sodium and potassium. This finding indicates that the polycystin complex gains unique ion channel properties from the assembly of PC1 and the resulting PC1/PC2 channel plays a key role in kidney physiology and ADPKD. In this multi-PI application, we will use our newly developed gain-of-function (GOF) PC1/PC2 channel mutant to determine how the PC1/PC2 ion channel function is regulated at a molecular level by extracellular and intracellular domains and how Ca2+ plays a role in this regulation. We will develop a new ADPKD mouse model that is defective in PC1/PC2 ion channel function and use it to determine that the channel function is essential for proper kidney development and inactivation of this function is the real culprit for ADPKD. To determine whether enhancing the PC1/PC2 ion channel function can be used as a therapeutic strategy, we will develop another new mouse model with the GOF of PC1/PC2 channel function and use it to determine that it can rescue the disease in a PKD1 mutant mouse that mimics human ADPKD. We anticipate that the proposed studies will provide new insights into the fundamental molecular mechanism of function and regulation of the PC1/PC2 channel and define its channel function as the key determinant of ADPKD. Overall, the project will likely lead to a better understanding of normal kidney development, reveal the primary culprit for developing ADPKD when PC1 or PC2 are mutated, and help form the basis for targeting the PC1/PC2 channel for preventative and therapeutic purposes.
Project Title: Ion Channel Function and Regulation of the Polycystin-1/2 complex in Kidney Physiology and Polycystic Kidney Disease Project Narrative: Despite the clear linkage between polycystin-1/polycystin-2 (polycystin-1/2) ion channel protein complex and polycystic kidney disease (PKD), the function and regulation of this complex and the role of its ion channel activity in kidney cyst formation is largely unknown. This multi-PI project will provide critical insights into the fundamental molecular mechanism of the polycystin-1/2 channel function and regulation, and discover its requirement in ensuring normal kidney development and preventing cyst formation. It is expected that the proposed studies will lead to a better understanding of PKD pathogenesis and help form the basis for targeting the polycystin-1/2 channel for preventive and therapeutic purposes.
