Role of Nonmuscle Myosin II in Membrane Trafficking and Organ Function

Cellular/membrane trafficking pathways that involve receptor mediated signaling, paracrine and endocrine function, nutrient uptake and membrane turnover are essential for cell survival and organ function. Recently, we identified Nonmuscle Myosin II (MII) as a critical regulator of compensatory and constitutive clathrin mediated endocytosis in neurons and fibroblasts. MII is an actin binding motor protein with important roles in cell migration, adhesion, division and brain and heart development .We hypothesize that MII is a crucial regulator of membrane trafficking events in cellsand there by regulates organ function. Cells that require rapid and efficient membrane trafficking are present in kidney and brain and point mutations in Myh9, gene encoding MIIA, lead to end stage kidney disease in humans. We hypothesize that the underlying mechanism in certain kidney diseases is abnormal MII mediated membrane trafficking in the renal tubular cells and podocytes. To determine the possible roles for MII in membrane trafficking and kidney function, we propose to employ two different approaches – 1) generate and characterize kidney function of mouse models harboring genetic inactivation of Myh9 and Myh10 genes in kidney specific cell types and also perform in vitro cell biological analysis of membrane trafficking pathways podocytes and renal tubular cells and 2) protein biochemistry approach to identify novel interacting partners for MII in live kidney specific cell types. The studies proposed here will provide substantial evidence for the role of MII in postnatal organ function and membrane trafficking events in cells. The novel molecular mechanisms we uncover from this study will help us understand the underlying mechanisms in renal tubular disorders and certain trafficking related renal diseases.