? ? Localized protein synthesis provides a means for the distal processes of the neuron to rapidly and autonomously respond to its environment. Although best characterized in the dendritic compartment, work over the past 5 years has proven that axons are capable of locally generating new proteins. In dendrites, activity-dependent local protein synthesis plays a role in synaptic plasticity. There is also evidence for activity-dependent protein synthesis in axons. Given the complex population of proteins synthesized in axons, it is likely that axonally synthesized proteins also play a role in the function of mature axons. The central hypothesis of this proposal is that changes in local protein synthesis in sensory axons alter the neuron's capacity for propagating noxious stimuli. The objective of this proposal is to understand how axonal transport and local protein synthesis contribute to hyperexcitability exhibited by damaged neurons leading to neuropathic pain states. We will use in vitro and in vivo methods to determine if the transport and sub-axonal localization of ion channel and neurotpeptide mRNAs are altered in neuropathic pain, and whether locally synthesized ion channels are functionally inserted into axoplasmic membranes and if this translation and trafficking are altered by neuropathic pain-associated stimuli. We will utilized chimeric mRNA reporter constructs to address axonal localization of these transcripts, both in cultured primary sensory neurons and in transgenic mice. GFP-tagged fusion proteins of locally synthesized ion channel proteins will be used to determine the functional relevance of axonally synthesized ion channels, with the ultimate goal of understanding how axonal trafficking and local synthesis of these proteins contributes to neuropathic pain. Neuropathic pain, the chronic pain experienced following injury, infection, or inflammation of peripheral nerves, sharply contrasts with normal pain, both is the molecular mechanisms which cause it and in their responses to conventional pain treatments. Current animal models of nerve trauma have provided some insights into the neuronal changes that occur in response to peripheral nerve damage - revealing a remarkable degree of plasticity in both the sensory neurons and spinal cord. Understanding how axonal transport and local protein synthesis contribute to increased hyperexcitability of these damaged sensory neurons may point to alternative methods of treating pathological pain states. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Nursing Research (NINR)
Type
Career Transition Award (K99)
Project #
5K99NR010797-02
Application #
7492307
Study Section
Special Emphasis Panel (ZNS1-SRB-M (44))
Program Officer
Marden, Susan F
Project Start
2007-09-04
Project End
2010-02-28
Budget Start
2008-06-01
Budget End
2010-02-28
Support Year
2
Fiscal Year
2008
Total Cost
$86,940
Indirect Cost
Name
Alfred I. Du Pont Hosp for Children
Department
Type
DUNS #
038004941
City
Wilmington
State
DE
Country
United States
Zip Code
19803
Willis, Dianna E; Wang, Meng; Brown, Elizabeth et al. (2016) Selective repression of gene expression in neuropathic pain by the neuron-restrictive silencing factor/repressor element-1 silencing transcription (NRSF/REST). Neurosci Lett 625:20-5
Ma, Thong C; Barco, Angel; Ratan, Rajiv R et al. (2014) cAMP-responsive element-binding protein (CREB) and cAMP co-regulate activator protein 1 (AP1)-dependent regeneration-associated gene expression and neurite growth. J Biol Chem 289:32914-25
Vuppalanchi, Deepika; Merianda, Tanuja T; Donnelly, Christopher et al. (2012) Lysophosphatidic acid differentially regulates axonal mRNA translation through 5'UTR elements. Mol Cell Neurosci 50:136-46
Overman, Justine J; Clarkson, Andrew N; Wanner, Ina B et al. (2012) A role for ephrin-A5 in axonal sprouting, recovery, and activity-dependent plasticity after stroke. Proc Natl Acad Sci U S A 109:E2230-9
Ben-Yaakov, Keren; Dagan, Shachar Y; Segal-Ruder, Yael et al. (2012) Axonal transcription factors signal retrogradely in lesioned peripheral nerve. EMBO J 31:1350-63
Donnelly, Christopher J; Willis, Dianna E; Xu, Mei et al. (2011) Limited availability of ZBP1 restricts axonal mRNA localization and nerve regeneration capacity. EMBO J 30:4665-77
Willis, Dianna E; Xu, Mei; Donnelly, Christopher J et al. (2011) Axonal Localization of transgene mRNA in mature PNS and CNS neurons. J Neurosci 31:14481-7
Willis, Dianna E; Twiss, Jeffery L (2011) Profiling axonal mRNA transport. Methods Mol Biol 714:335-52
Vuppalanchi, Deepika; Coleman, Jennifer; Yoo, Soonmoon et al. (2010) Conserved 3'-untranslated region sequences direct subcellular localization of chaperone protein mRNAs in neurons. J Biol Chem 285:18025-38
Willis, Dianna E; Twiss, Jeffery L (2010) Regulation of protein levels in subcellular domains through mRNA transport and localized translation. Mol Cell Proteomics 9:952-62

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