Primary Appointment

 Overview of Research Interests  Multicellular organisms have evolved a variety of tissue repair responses to cope with tissue damage.  Some of these responses (wound closure) are aimed at restoring structure and function to the damaged tissue(s) while others (inflammation and nociceptive sensitization) are aimed at protecting the organism from further infection or injury. My laboratory is interested in identifying the elusive signals that initiate and terminate different aspects of the organismal tissue repair response, as well as the genes that are required to execute each specific response.  Ultimately, we wish to understand in molecular detail how the activities of diverse damage-responsive cell types are coordinated in space and time to give a functional tissue repair program. To pursue these interests we have developed a variety of tissue repair/response assays in the highly genetically tractable model organism, Drosophila melanogaster and are focusing our efforts on three critical responses: epidermal wound closure, inflammation (recruitment of blood cells to the site of injury), and nociceptive sensitization (lowering of the threshold for sensing painful stimuli following injury).  Given that tissue repair responses are an ancient survival mechanism of multicellular animals, we expect that the functional importance of many of these genes we identify will be conserved between flies and vertebrates. Below is a summary of some of the projects ongoing in the lab. 

 Cellular and genetic analysis of epidermal wound closure and wound-induced epidermal cell-cell fusion: 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 the performance of large-scale genetic screens designed to identify the complement of Drosophila genes that are required for various steps of epidermal healing. These screens are ongoing.

 Cellular and genetic analysis of wound-induced inflammation (blood cell recruitment):   Circulating blood cells are rapidly recruited to epidermal wound in Drosophila larvae (PNAS, 2008). Remarkably, this recruitment occurs through a similar cellular mechanism (adhesive capture) as in vertebrates. We have created transgenic larvae that permit simultaneous live monitoring of the epidermal wound and circulating blood cells and we are now using these larvae to perform a genetic screen for blood cell factors required for proper adhesion to the wound site. We are hopeful that this approach will allow us to identify adhesion proteins responsible for binding of blood cells to damaged tissue- these factors may represent pattern-recognition receptors for “altered self” tissue.

 Establishment of 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 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). We are currently using genetic and cell biological approaches to define the molecular consequences of activating the TNF-receptor in sensory neurons so that we can understand how tissue damage leads to adaptive alterations in the behavioral response threshold of nociceptive sensory neurons.

Last updated: 10/2/2009