We are interested in probing the function of proteins that allow the kidneys to regulate body fluids and maintain the proper balance of ions in the blood. To function properly, kidney cells rely on a variety of proteins that sense and respond to the chemical composition, mechanical pressure, and fluid flow rates in the plasma and urine. In our lab, we determined the three-dimensional structure of one of these proteins, called PKD2, which cooperates with a partner protein, PKD1, to form a molecular signal-transduction machine. Although mutations in these proteins underlie a life-threatening form of kidney disease, very little is known about their mechanism of action. Using state-of-the-art methods in cell, molecular, and structural biology, biochemistry, and pharmacology, we will search for small molecules, peptides, and antibodies that regulate the activity of the PKD1/2 complex. These molecular tools will allow us to determine how PKD2 is regulated by PKD1 and how the activated complex passes the signal along—providing a starting point for the development of treatments for kidney disease.