Grant: Project Grant

Kidney stones are common, painful and expensive to treat. The most common risk factor for kidney stones is peeing too much calcium. The primary goal of this proposal is to understand why some individuals pee too much calcium, thereby increasing their risk for a kidney stone. To do this we are examining the cause of a rare disease in a child who as part of her disease pees too much calcium. We have found that she has a mutation in a gene called FAM111A. Our preliminary work tells us that this gene when made into a protein, regulates how much of the cell sensor for calcium is present. Specifically it decreases the amount of this receptor, known as the calcium sensing receptor (CaSR), in special kidney cells. When it is mutated, i.e. not functional, there is too much of this receptor at the surface and it tells the kidney to pee more calcium. We are going to examine how this is occurring in cells and make an animal model of her disease to test new treatments on. The other aspect of this work is to determine how the CaSR signals in a specific part of the kidney (the thick ascending limb, TAL) to prevent calcium from getting back into the blood and therefore ending up in the urine. We have created a model system that senses this signalling and will tease out the specific signals that activate this. We will also directly look at this signalling in TALs we have dissected and kept alive via a technique called renal tubular microperfusion. We are one of only a few laboratories in the world that can do this. Together these studies will provide much needed new information about what causes people to pee too much calcium and therefore potential drug targets for the treatment of persons with kidney stones.