Grant: Project Grant

Kidneys act as a barrier that filters water and waste products into urine while retaining important proteins in blood. When this barrier is damaged, massive leakage of proteins into urine (proteinuria) occurs, leading to a condition known as nephrotic syndrome. Idiopathic nephrotic syndrome (INS) is a common cause of nephrotic syndrome in children and it also affects adults. The precise cause of INS is unknown, preventing us from identifying specific treatments. Patients with INS respond to immuno-suppressive drugs. Therefore, dysfunctional immune system is likely a cause of INS. However, the kidney of INS patients does not show typical signs of inflammation with immune cells, making it a "mysterious disease". Importantly, there is no good animal model of INS. This major limitation has kept us in dark for five decades regarding the precise cause of the disease. Recently, a new concept is emerging that the immune system in INS patients may be making antibodies that attack the kidney. We will test if this concept is true, and if so, which proteins in the kidney are targeted by the immune system. Using the novel mouse model we developed, we will test if kidney-attacking antibodies are responsible for the disease. We will also use the cultured cells and kidney organoids and test how the antibodies affect the function of the specific kidney cell (called podocyte) that is responsible for the barrier function. Finally, we will use the state-of-the-art technology to find which immune cells in patients' blood are responsible for generating these self-attacking antibodies. If successful, the results will be transformative; we will establish INS as an autoimmune disease, identify which proteins are targeted in the kidney, and which cells are responsible. In the long-term, the results will help identifying biomarkers that allow more accurate diagnosis, and disease-causing cells that can be targeted by personalized, novel, and safer therapies for INS patients.