Multicellular organisms have evolved mechanisms to protect damaged tissue while it heals. One mechanism is a form of sensory neuron plasticity called nociceptive sensitization. This sensitization can manifest as aversive withdrawal to previously non- noxious stimuli (allodynia). Despite its biological and clinical importance, the genes required for nociceptive sensitization remain obscure. This research project focuses on the molecular genetic control of nociceptive sensitization in a model genetic organism where gene discovery is greatly facilitated. Our guiding hypothesis is that there is a conserved molecular genetic machinery that initiates, regulates, executes, and terminates nociceptive sensitization. To test this hypothesis we have established a nociceptive sensitization assay using Drosophila larvae and demonstrated that development of thermal allodynia requires the Drosophila homolog of the tumor necrosis factor (TNF) receptor and seventeen other genes we identified in a genetic screen for sensitization mutants. For this screen we tested whether larvae expressing gene-specific inhibitory RNAi transgenes specifically in nociceptive sensory neurons could develop allodynia normally following UV irradiation of the barrier epidermis. Our long-term objective is to use our unique assays and genetic tools to identify the complement of genes required in nociceptive sensory neurons for development of allodynia and to determine the specific function of these genes during sensitization. Our shorter-term goals are enumerated in the following specific aims: 1. To test the hypothesis that physical tissue damage (wounding) induces allodynia through different signals and mediators than UV-induced tissue damage. 2. To test the hypotheses that TNF induction following UV irradiation is apoptosis-independent, transcriptional, and/or translational/post-translational. And, 3. To characterize and identify novel genes required for nociceptive sensitization by expanding our genetic screen. This project represents the first systematic study of nociceptive sensitization in a model genetic organism and has great potential for uncovering the genes that initiate, execute, and regulate this process. Given the conservation of genes required for most fundamental neuronal functions we expect that this project will inform our understanding of nociceptive sensitization in vertebrates and in pathophysiological states, such as cancer and chronic pain syndromes, where this form of sensory neuron plasticity is thought to be improperly activated or regulated.

Public Health Relevance

This research project employs a model genetic organism, the fruit fly, to uncover the genetic control of nociceptive (pain) sensitization, a process of immediate relevance to human health. Nociceptive sensitization is critical for organisms to protect sites of tissue injury, such as those caused by trauma or surgery, while they heal. Given the conservation of genes required for most fundamental biological processes, including neuronal function, we expect that this project will inform our understanding of nociceptive sensitization in vertebrates and in pathophysiological states, such as cancer and a variety of chronic pain syndromes, where the sensitization response is thought to be improperly activated or regulated.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS069828-03
Application #
8228126
Study Section
Molecular Neurogenetics Study Section (MNG)
Program Officer
Porter, Linda L
Project Start
2010-02-15
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
3
Fiscal Year
2012
Total Cost
$283,919
Indirect Cost
$99,556
Name
University of Texas MD Anderson Cancer Center
Department
Biochemistry
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Turner, Heather N; Galko, Michael J (2014) Macrophages gain a partner at the table: epidermal cells digest peripheral dendritic debris in Drosophila. Neuron 81:465-7
Im, Seol Hee; Galko, Michael J (2012) Pokes, sunburn, and hot sauce: Drosophila as an emerging model for the biology of nociception. Dev Dyn 241:16-26
Babcock, Daniel T; Shi, Shanping; Jo, Juyeon et al. (2011) Hedgehog signaling regulates nociceptive sensitization. Curr Biol 21:1525-33