MOLECULAR GENETIC ANALYSIS OF WOUND HEALING--DROSOPHILA

Duke University, Durham NC

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Abstract

Trauma that results in loss of tissue or tissue integrity constitutes a wound, and initiates a wound healing or repair process. Key features of that process include achieving immediate tissue homeostasis, repelling microorganisms and ultimately, the restoration of normal tissue physiology. Wounding and wound healing in humans is of considerable biological and social significance. Wounds occur by accident, can be inflicted in anger, or occur during surgery, for beneficial medical reasons. The ultimate goal of the work we propose is to understand the basic biology of epithelial response to wounds with the long range goal of contributing to the design of intervention strategies designed to speed healing or prevent excessive scarring. A number of vertebrate, and especially mammalian, animal model systems have been developed to study wounding and wound healing. As a consequence, the molecular players responsible for proper wound healing have begun to be identified. Recently, knockout and transgenic mouse technologies have been applied to the study of wound healing. Nevertheless, mammalian model systems can be used in wounding studies only after careful ethical consideration, are naturally time consuming and are very expensive. Moreover, forward genetic screens are essentially impractical. Here, we propose to pursue molecular/genetic strategies that are uniquely available in Drosophila to investigate the biology of wounding and wound healing. Recently we used mechanical and laser methods to ablate tissue in Drosophila embryos and found that such ablations are followed by rapid and robust healing. Moreover, we found that healing was completely inhibited in embryos homozygous for defects in the structural gene for myosin heavy chain. We propose to characterize wounding and wound healing in Drosophila, test the role of candidate loci in the process of wounding and wound healing, and perform forward genetic screens to recover loci that fail to heal properly. These studies will address directly those aspects of epithelial wound healing that are conserved over the 0.5 to 1 billion years of evolution that separate insects from mammals. Together, they promise to bring the powerful tools of Drosophila genetics and molecular genetics to bear on this important biological problem.