Research
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 (PNAS, 2008), epidermal cell orientation and fusion (Current Biology, 2015), 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, 2012; Developmental Biology, 2017) required for wound closure and to expand our efforts into epigenetic regulation of wound closure (Regeneration, 2014) and regulation of cell adhesion dynamics at the wound edge (Development, 2019)
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; Cell Death and Disease, 2017). Our most interesting finding to date is that the conserved Hedgehog signaling pathway, which regulates diverse aspects of patterning and cell fate specification during both fly and vertebrate development, also plays a conserved role in regulating the responses of sensory neurons to painful stimuli (Current Biology, 2011; eLife, 2015). We continue to explore the mechanisms of action of these two signaling pathways.
We also continue to develop new assays for how Drosophila larvae respond to noxious cold (Current Biology, 2016; PLoS One, 2018), harsh mechanical touch (Journal of Neuroscience, 2019), and chemical exposure (Philosophical Transactions of the Royal Society, 2019). We have also developed a promising new Drosophila model of diabetes-associated pain (Disease Models and Mechanisms, 2018) using seed research money awarded through and MD Anderson R. Lee Clark basic science fellowship.
We expect that our efforts on wound closure and pain sensitization, because they focus on biomedically important biology and conserved genes, will eventually lead to clinically actionable insight for human patients.
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. Pain hypersensitivity is a major clinical issue with cancer and cancer treatment.
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; Cell Death and Disease, 2017). Our most interesting finding to date is that the conserved Hedgehog signaling pathway, which regulates diverse aspects of patterning and cell fate specification during both fly and vertebrate development, also plays a conserved role in regulating the responses of sensory neurons to painful stimuli (Current Biology, 2011; eLife, 2015). We continue to explore the mechanisms of action of these two signaling pathways.
We also continue to develop new assays for how Drosophila larvae respond to noxious cold (Current Biology, 2016; PLoS One, 2018), harsh mechanical touch (Journal of Neuroscience, 2019), and chemical exposure (Philosophical Transactions of the Royal Society, 2019). We have also developed a promising new Drosophila model of diabetes-associated pain (Disease Models and Mechanisms, 2018) using seed research money awarded through and MD Anderson R. Lee Clark basic science fellowship.
We expect that our efforts on wound closure and pain sensitization, because they focus on biomedically important biology and conserved genes, will eventually lead to clinically actionable insight for human patients.