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Molecular Genetics of Pain Signaling Laboratory
Our laboratory uses the powerful genetics of Drosophila melanogaster to study fundamental problems of neurobiology. The Drosophila model system has opened the door to molecular analysis of virtually every area of neurobiology. The list of accomplishments by workers in the Drosophila field are too numerous to list, but here are a few highlights: the shaker mutant led to the cloning of the first potassium channel, Drosophila mutants with defective circadian rhythms have led to an understanding of the molecular clocks that drive our sleep and waking, even the complex processes of learning and memory have been illuminated by the isolation and cloning of Drosophila genes required for these processes.
The long term goal of the lab is to identify the genes that are responsible for pain signaling. We use Drosophila to discover the genes and we hope to ultimately provide novel therapeutic targets for the treatment of human pain. Projects in the lab range from the level of the organism to the level of the molecule. Various techniques are employed: behavioral analysis, molecular genetics, biochemistry, confocal microscopy, electrophysiology, and functional imaging.
We have discovered that the Drosophila larva produces a stereotyped behavioral output in response to a variety of stimuli that are considered painful by humans and rodents. The normal pattern of larval locomotion resembles the familiar movement rhythmic motor pattern of a caterpillar. A peristaltic rostral to caudal wave of muscular contraction propels the larva forward. A light touch, causes the larva to pause its motion but then continue on its way. In contrast, a light touch of a probe heated above 39°C causes the larva to produce a writhing escape response.
To identify the molecules that allow the larva to detect the noxious heat stimulus. We have performed genetic screens to identify mutants that fail to show the wild type writhing escape response when touched with the hot probe. These mutants are a subject of future study in the lab. Since the Drosophila genome has been fully sequenced, and since the mutants in our screen were created by transposable elements, the cloning process is straightforward.
A major focus of the lab is a gene we have named painless. painless mutant larvae respond to the heated probe as if it were simply producing a light touch. The painless gene encodes an ion channel of the TRP family. Remarkably, mammalian homologues of the painless gene are specifically expressed in pain sensing neurons. Mammalian painless homologues are activated by compounds that produce a sensations of burning pain such as wasabi (Japanese horseradish)cinnamon, and raw garlic.
The painless gene is expressed in sensory neurons that are just beneath the epidermis of the larva. We hypothesize that these neurons, called multi-dendritic (md) neurons are the "pain sensors." Another major interest of the lab is to understand structure function relationships and the developmental biology of these cells.
Potential projects for graduate students and postdocs include characterization of new pain signalling mutants that we have isolated. Other projects include functional imaging of md neurons expressing genetically encoded calcium sensors, mapping brain circuits involved in the “perception of pain” and functional analysis of the Painless protein.
Representative Publications
- Tracey W.D., Wilson R.I., Laurent G., Benzer S. (2003). painless, a Drosophila gene essential for nociception. Cell Apr; 13(2):261
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Daniel Tracey, PhD
Director, Molecular Genetics of Pain Signaling Laboratory
Office: (919) 681-4717
E-mail: trace006@mc.duke.edu
Laboratory staff members:
Nancy Stearns, Research Specialist.
Angela Hofhine, Research Technician
Lixian Zhong, Graduate Student (Program in Pharmacology)
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