The wound repair mechanisms that heal a hole in a single cell and those that close a multicellular wound operate on massively different scales but both are critical for survival and involve a series of ancient and highly conserved processes. Cell and tissue repair is thus of both fundamental cell biology interest and significant clinical relevance. The general aim of this proposal is to understand the cellular and molecular mechanisms of single cell and multicellular wound repair and their ensuing biological manifestations, such as the induction of an inflammatory response, within the in vivo context of a whole organism. We are particularly interested in the regulation of the actin cytoskeleton and in the role of the Rho family of small GTPases in these processes. This study proposes to investigate the mechanisms of wound repair in Drosophila in order to utilize its superb genetic tractability and amenability for live imaging not available in current wound healing models. We have recently developed a wound healing model in Drosophila embryos that allows easy comparison of repair in wildtype versus embryos mutant for candidate wound genes, and that makes it possible to screen for novel genetic players in the repair process.
The specific aims of this proposal are to determine the biological basis of single cell and tissue (multicellular) wound repair, and to determine how the associated inflammatory response is regulated, as well as what its influence might be on the outcome of wound repair. Our long-term goal is to understand precisely the players and events that regulate the wound healing and inflammatory responses in order to guide further design of tissue repair therapies to enhance healing speed and prevent scarring. As the artificially-induced movements of wound repair share many similarities with normal morphogenetic events, the properties we learn here will impact our understanding of the basic biological events and regulations that underlie morphogenesis. Our studies will also be of fundamental clinical significance in many disease situations besides simply that of skin repair since a number of other pathologies ranging from lung and kidney fibrotic diseases to even heart disease and cancer are related to an aberrant inflammatory response. Controlling repair and inflammation will also be a fundamental consideration in tissue engineering where artificial and/or cell based constructs are implanted to reconstruct tissues.
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