Mechanisms of Nociceptive Neuronal Plasticity

Project: Research project

Project Details

Description

DESCRIPTION (provided by applicant): It is now recognized that inflammation or peripheral nerve injury induces functional and structural modifications in sensory neurons and thereby alters nociceptive transmission. The changes in gene expression triggered by chronic inflammation or nerve injury are thought to play an important role in the initiation, development and maintenance of these alterations. However, little is known about the mechanisms controlling such changes in gene expression, particularly with respect to the nuclear proteins that regulate this process. To address this question, we have hypothesized that expression patterns of certain ehromatinassociated Polycomb- (PcG) and trithorax-group (trxG) genes are changed in sensory neurons after nerve injury and/or inflammation. In Drosophila, as well as in mammals, these genes are part of the cellular memory system that controls stable expression patterns of target genes. We believe, this application is innovative because our preliminary data are the first, to our knowledge, to demonstrate that certain PcG and/or trxG genes undergo selective and differential regulation in sensory neurons in distinct models of neuropathic pain. Thus, the application has potential for high scientific impact, because regulated PcG and/or trxG could control persistent nociceptive neuronal plasticity during inflammatory and/or neuropathic pain states. Our specific aims will: 1) Determine the expression levels and cell-type distribution of PcG and trxG genes in adult rat dorsal root ganglia (DRG) and trigeminal ganglia (TG) under control conditions (i.e. uninjured and uninflamed). 2) Characterize changes in the expression levels and cell-type distribution of PcG and trxG genes in DRG and TG in animal models of chronic inflammatory and neuropathic pain. 3) Determine whether over/under-expression of certain PcG and/or trxG gene products elucidated in Specific Aim #2 modulates the secretion of nociceptive neurotransmitters in primary TG culture. The multimethodological approach outlined in this proposal should help to identify and characterize the chromatin-associated PcG and/or trxG nuclear factors regulated by chronic inflammation and/or peripheral nerve injury. The knowledge gained by these studies not only should open new avenues of research on the molecular and cellular mechanisms responsible for persistent nocieeptive neuronal plasticity during clinical pain states, but also may provide a novel strategy for modifying the activity of nociceptors using gene and/or drug therapy via the targeting of PcG and trxG nuclear factors.
StatusFinished
Effective start/end date5/1/034/30/05

Funding

  • National Institutes of Health: $146,000.00
  • National Institutes of Health: $146,000.00

ASJC

  • Medicine(all)
  • Dentistry(all)

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