Role of myosin 1e in podocyte biology and renal filtration

Chronic kidney disease is a major public health concern in the US and worldwide. Myosin 1e (Myo1e), an actin-dependent motor protein expressed in glomerular visceral epithelial cells (podocytes), is necessary for normal glomerular filtration in humans and mice. Myo1e is one of the components of the slit diaphragms, protein complexes that connect adjacent podocytes and play a key role in selective protein filtration in the glomerulus. Inactivating mutations in Myo1e are associated with focal segmental glomerulosclerosis (FSGS), one of the leading causes of end stage renal disease. In this proposal, we will determine how actin-dependent motor activity of Myo1e contributes to the maintenance of normal glomerular architecture and functions. We hypothesize that Myo1e is necessary for podocyte adaptation to the changes in their environment, including changes caused by high blood pressure and other pathological conditions, via its role in regulating membrane tension and slit diaphragm stability. In this application, we propose to study the role of Myo1e in tension generation and slit diaphragm turnover using innovative biophysical and cell biological approaches. In Aim 1, we will determine how Myo1e-mediated tension regulates podocyte activity and allows podocytes to adapt to the changing environment within the glomerulus under normal and pathological conditions. In Aim 2, we will dissect Myo1e role in regulating slit diaphragm assembly and turnover. In Aim 3, we will analyze the mechanisms responsible for regulation of Myo1e expression and activity. These studies will help determine how mutations in Myo1e contribute to development of FSGS and provide better understanding of the regulation of podocyte structure and function.