A thorough understanding of the molecular machinery that operates in nociceptive sensory neurons will lead to greater understanding of the protective molecular mechanisms of acute pain. To identify nociception molecules, we previously carried out a genetic screen for nociception defective mutants using the fruitfly Drosophila melanogaster. This led to our discovery of the painless gene, which shows enriched expression in nociceptive sensory neurons and is required for acute nociception. The painless gene, as well as a related gene named dTRPA1, encode homologues of TRPA1. Human mutations in TRPA1 mutations lead to familial episodic pain syndrome (FEPS) and TRPA1 is highly expressed in nociceptor neurons. We have identified pickpocket as a critical regulator of mechanical nociception which is specifically expressed in Drosophila nociceptors. The purpose of this proposal is to identify other genes expressed in nociceptor neurons of Drosophila and to test the functional requirement of those genes in nociception. Building upon our recent studies that identified the Class IV multidendritic neurons as polymodal nociceptors of the Drosophila larva we will: 1) Determine the complete transcriptome of nociceptive Class IV multidendritic neurons. 2) Test the functional requirement of genes with enriched expression in nociceptive sensory neurons using tissue specific RNAi knockdown in these cells in vivo. 3.) Functionally characterize a subset of novel genes that we identify to be essential for nociception in Aims 1 and 2. In the short term, these studies will provide critical insight into molecular and cellular mechanisms of nociception using a high throughput approach that is made possible using Drosophila. In the long term, these studies may eventually allow for the identification of evolutionarily conserved mechanisms that contribute to human nociception. !

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM086458-02
Application #
8296690
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Sesma, Michael A
Project Start
2011-07-05
Project End
2015-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
2
Fiscal Year
2012
Total Cost
$298,300
Indirect Cost
$108,300
Name
Duke University
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Honjo, Ken; Mauthner, Stephanie E; Wang, Yu et al. (2016) Nociceptor-Enriched Genes Required for Normal Thermal Nociception. Cell Rep 16:295-303
Mauthner, Stephanie E; Hwang, Richard Y; Lewis, Amanda H et al. (2014) Balboa binds to pickpocket in vivo and is required for mechanical nociception in Drosophila larvae. Curr Biol 24:2920-5
Pagadala, Promila; Park, Chul-Kyu; Bang, Sangsu et al. (2013) Loss of NR1 subunit of NMDARs in primary sensory neurons leads to hyperexcitability and pain hypersensitivity: involvement of Ca(2+)-activated small conductance potassium channels. J Neurosci 33:13425-30
Stewart, Andrea; Tsubouchi, Asako; Rolls, Melissa M et al. (2012) Katanin p60-like1 promotes microtubule growth and terminal dendrite stability in the larval class IV sensory neurons of Drosophila. J Neurosci 32:11631-42
Honjo, Ken; Hwang, Richard Y; Tracey Jr, William Daniel (2012) Optogenetic manipulation of neural circuits and behavior in Drosophila larvae. Nat Protoc 7:1470-8