Role of a conserved miRNA regulatory axis in neuropathic pain

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Neuropathic pain is a poorly treated medical condition of enormous public health importance. One mechanism by which nerve injury leads to neuropathic pain is by altering the expression of numerous proteins that regulate neuronal excitability. MicroRNAs (miRNAs) are key modulators of protein synthesis, and nerve injury alters the neuronal expression of many individual miRNAs. miRNAs function by reducing the stability and/or translation of target messenger RNAs (mRNAs) that contain binding sequences with partial complementarity to the miRNAs. A single miRNA can thereby repress the synthesis of many proteins. However, miRNAs themselves are coordinately regulated by upstream control pathways. One such pathway involves Lin28a and Lin28b, RNA binding proteins that selectively and coordinately suppress the biogenesis of the Let-7 family of miRNAs, which are amongst the most abundant miRNAs in differentiated tissues. Since many Let-7 miRNA targets encode proteins involved in growth and regeneration, increased Lin28 signaling promotes pro-growth programs of protein synthesis. Indeed, Let-7 miRNAs have been implicated as possible regulators of axon growth and nerve regeneration. Yet, the directions and cell type specificity of these effects remain unclear, as does the potential involvement of Lin28. Furthermore, the possibility that the Lin28/Let-7 pathway contributes to the severity or duration of neuropathic pain remains entirely unexplored. Here, we outline plans to directly tackle these questions, through a multidisciplinary approach. In Aim 1, we will map the spatiotemporal patterns and cell type specificity of changes in the expression of Let-7 miRNAs and Lin28 in three complementary mouse models of neuropathic pain. In Aim 2, we will utilize mouse genetics and adeno- associated virus mediated gene transfer, along with behavioral and in vivo electrophysiological approaches, to increase or ablate Let-7 miRNAs or Lin28 protein expression selectively in peripheral neurons or glia, to assess the functional importance of the Lin28/Let-7 pathway to the initiation, maintenance, and reversal of neuropathic pain. Finally, in Aim 3, we will combine bioinformatics and proteomic approaches to define the programs of altered protein expression following nerve injury that depend upon the Lin28/Let-7 pathway, and that might underlie the contributions of this pathway to neuropathic pain. Together, these studies will help to define the roles of the Lin28/Let-7 pathway in neuropathic pain and provide important information regarding when, where, and in what cell type this master regulatory pathway might be therapeutically targeted to alleviate pain.