Drosophila genetics Tissue repair Pain sensitization Cell migration

Cellular and genetic analysis of epidermal wound closure responses: To study epidermal healing we developed wound healing assays using Drosophila larvae (PloS Biology, 2004) and showed that epidermal repair proceeds by a similar sequence of steps and involves functionally equivalent cell types to those in vertebrates. Some of the hallmarks of the Drosophila repair process include recruitment of blood cells, epidermal cell orientation and fusion, epidermal activation of the Jun N-terminal kinase (JNK) signaling pathway, JNK-dependent reepithelialization of the wound site, and clearance of cell debris and scab material. Recently, we developed transgenic larvae that allow live visualization of epidermal wound responses and enable screening for the complement of Drosophila genes that are required for various steps of epidermal healing (Genetics, 2010). We also identified a conserved receptor tyrosine kinase and ligand (Current Biology, 2009), related to the Vascular Endothelial Growth Factor Receptor signaling cassette, that are required for healing. Our genetic screen is an ongoing effort and we continue to identify new genes (Journal of Cell Science, 2013) as well as characterize the mechanism of action of genes that we have previously identified. In a relatively new effort we have begun to look at the epigenetic regulation of wound closure (Regeneration, 2014).

A genetically tractable model of tissue damage-induced nociceptive sensitization: Local alterations in nociception (pain sensation) are a hallmark of tissue damage in vertebrate organisms. Nociceptive sensitization can involve a lowering of the pain threshold such that previously non-noxious stimuli are perceived as painful (allodynia), as well as a faster or exaggerated response to supra-threshold stimuli (hyperalgesia). Sensitization serves to foster escape behaviors that protect sites of tissue damage while they heal. We have shown that both hyperalgesia and allodynia develop following UV irradiation in Drosophila larvae and that allodynia depends on a conserved tumor necrosis factor (TNF)-like cytokine that is produced by the irradiated epidermal cells and on a TNF receptor-like protein present on nociceptive sensory neurons (Current Biology, 2009). Since this initial demonstration that nociceptive sensitization can be modeled in Drosophila we have been using the full genetic power of this system to identify new assays (JoVE, 2012) and new genes (Current Biology, 2011) that regulate nociceptive sensitization. Our most interesting finding to date is that the Hedgehog signaling pathway, which regulates diverse aspects of patterning and cell fate specification during development, also plays a conserved role in regulating the responses of sensory neurons to painful stimuli (Current Biology, 2011). We are continuing to study the mechanisms of TNF- and Hh-induced sensitization, to screen for new genetic regulators of thermal allodynia and hyperalgesia, and to develop new assays for how Drosophila larvae respond to noxious cold, harsh mechanical touch, chemicals, and chemotherapy drugs (MD Anderson Clark Fellowship Project).