Mechanisms of Dynamic Cytoskeleton and Membrane Interactions

About This Grant

PROJECT SUMMARY/ABSTRACT Dynamic interactions between intercellular membranes and the cortical cytoskeleton are critical for cell survival. During their normal functions, cells face physiological and environmental stresses that can lead to rupture of the plasma membrane and/or of the nuclear envelope. Rapid repair of such injuries, whether arising from daily activities or resulting from trauma, infection, or diseases such as cancer, is an active area of cell biology research. My lab has a long-standing track record in successfully identifying key molecules and elucidating their in vivo roles at the cell cortex necessary for the repair of plasma membrane and at the nuclear envelope necessary for repair of the nuclear cortex. The overall focus of the lab is to delineate how cells deal with such cell and/or nuclear cortex disruptions to efficiently and effectively repair the lesions. We have developed a robust inducible single cell repair model using the syncytial Drosophila embryo that has superb amenability for live imaging and genetic tractability that is unavailable in other cell wound repair models. We have also established a model for the newly appreciated nuclear export pathway (Nuclear Envelope budding) on the surface of Drosophila salivary gland and S2 cell nuclei that provides the same superb amenability for live imaging and genetic approaches. While both systems rely heavily on dynamic membrane and/or cytoskeleton/nucleoskeleton interactions, a major challenge in both of these systems is the absence of a molecular outline of the events occurring during the repair and/or export processes in any organism or system. Our goals during the proposed period are to establish the molecular framework underpinning these processes using a combination of state-of-the-art cell biological, genetic, developmental, biochemical, and high-resolution imaging approaches. Our studies are expected to be of significant medical relevance, as understanding the molecules, machineries, and pathways governing cell wound repair, NE-budding (nuclear export), and dynamic membrane-cytoskeleton/nucleoskeleton interactions will be extremely valuable for elucidating fundamental cellular mechanisms, as well as for developing new or enhancing existing strategies for treating conditions associated with cell/nuclear damage, and for disciplines such as regenerative medicine where cell based constructs are used to reconstruct tissues, clinical drug delivery systems where molecules cross cell membranes, and for virus nuclear egress.