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Investigating post-transcriptional mechanisms of neuropathic pain

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      Neuropathic pain is a chronic condition which can arise following damage to the somatosensory system and often involves both hyperalgesia and allodynia. The molecular mechanisms of neuropathic pain remain incompletely understood but require enduring alterations in specific gene program expression and protein synthesis affecting neuronal signaling and excitability. We investigate the roles of non-coding RNA regulatory pathways in impacting hyperalgesia and determining the mRNA complement recruited during the protein synthesis response in neuropathic pain. Nerve injury alters the expression of many miRNAs, including the highly conserved let-7 family miRNAs, which repress pro-growth mRNAs and are implicated in axon growth, neuronal plasticity, and brain circuit development. The Lin28 RNA binding protein can prevent maturation of let-7 precursor RNAs; consequently, increased Lin28 signaling promotes pro-growth gene expression. The regulation and potential roles role of Lin28/let-7 pathway in neuropathic pain remain largely unexplored. Using spared nerve injury (SNI) mouse models of neuropathic pain, we find in preliminary data that Lin28a loss of function in sensory neuron populations can result in a deficit in mechanical hypersensitivity post-surgery. In SNI and sciatic nerve transection (SNT) mouse models, we evaluate molecular mechanisms underlying pain using single molecule detection and genetic manipulation. A sensitive RNA imaging assays, RNAScope in situ hybridization (ISH), is used to amplify single RNA target signals in fixed tissues to allow mapping of the spatiotemporal patterns and cell type specificity of changes in non-coding RNA regulatory pathways. Digital PCR is used to provide sensitive and quantitative validation. We find lin28 mRNA level are elevated in injured dorsal root ganglion cells, injured sciatic nerves and their surrounding Schwann cells at 3 days post SNI and SNT surgery accordingly.
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