PROJECT SUMMARY/ABSTRACT Most cells of the body are exposed to a wide range of physiological and environmental stresses during their normal daily functions that can lead to disruption of the cell’s plasma membrane and underlying cortical cytoskeleton. The capacity of cells to repair general day-to-day wear-and-tear injuries, as well as ones resulting from trauma or pathological conditions ranging from infection to diseases/cancer, is essential for their survival. The general aim of this proposal is to understand how cells cope with these membrane and cortical cytoskeleton disruptions. We have developed a single cell repair model using the syncytial Drosophila embryo that is proving to be a superb model for the in vivo study of cellular repair owing to its amenability for live imaging and its genetic tractability that is unavailable in other cell wound repair models. Our long-term goal is to delineate the molecular and cellular mechanisms governing cell wound repair. The specific aims of this proposal are 1) to determine how a cell’s torn plasma membrane is rapidly re-sealed and remodeled; 2) to determine how the initial uniform repair signal results in the precise spatio-temporal recruitment of repair factors to the wound site; and 3) to determine the nature and regulation of the actin ring attachment to the overlying plasma membrane facilitating cell wound closure. Our findings should extrapolate across phyla, complement work being done in other experimental systems, provide new insight into key events of cellular repair, and impact work in other fields by contributing to the understanding of related fundamental cellular and developmental processes. While fundamental in nature, our studies will also be of significant medical relevance, as understanding the events controlling cell wound repair will be important for developing new strategies for treating cellular damage (or for augmenting the effectiveness of existing ones) or for disciplines such as regenerative medicine where cell based constructs are implanted to reconstruct tissues.