Project Abstract Long noncoding RNAs (lncRNAs) regulate gene expression. Peripheral nerve injury dysregulated their expression in the pain-related regions including dorsal root ganglion (DRG). However, the role of most identified lncRNAs in neuropathic pain is still uncertain. Identifying novel lncRNAs and exploring their contribution to neuropathic pain may provide novel strategies for management of this disorder. We recently used a next generation RNA sequencing approach and identified a large, native, full-length non-coding RNA in mice and human. Because it is expressed highly in the DRG, we named it as DRG specific long noncoding RNA (DS-lncRNA). Our preliminary data revealed that peripheral nerve injury downregulated DS-lncRNA likely due to a decrease in the expression of a transcriptional activator Pou4f3 in the injured DRG. Rescuing this downregulation attenuated the nerve injury-induced pain hypersensitivity, likely through blockade of the increased interaction between RALY (a transcription co-factor) and the RNA polymerase II (RNA II) and consequent silence of the RALY/RNA II-triggered expression of Ehmt2 mRNA and its coding protein G9a (a key player in neuropathic pain) in the injured DRG. Given that DS-lncRNA can directly bind to RALY, our preliminary results indicate that DRG DS-lncRNA downregulation is required for neuropathic pain likely through negative regulation of DRG RALY/RNA II-triggered G9a expression. This proposal will further examine whether and how DS-lncRNA contributes to neuropathic pain. In Specific Aim 1, we will first investigate whether rescuing downregulation of DS-lncRNA in the injured DRG attenuates neuropathic pain development and maintenance. We will then examine whether mimicking nerve injury-induced downregulation of DRG DS-lncRNA leads to neuropathic pain symptoms in the absence of nerve injury. In Specific Aim 2, we will examine whether peripheral nerve injury results in time-dependent downregulation of DS-lncRNA and its transcription factor Pou4f3 in the DRG. We will also examine whether DS-lncRNA downregulation is attributed to a decrease of Pou4f3 expression in the injured DRG after peripheral nerve injury. In Specific Aim 3, we will test the effect of DS-lncRNA on the expression of Ehmt2 mRNA, G9a and their downstream pain-related genes in the injured DRG after peripheral nerve injury. We will also determine whether DS-lncRNA downregulation enhances the binding of RALY to RNA II leading to RALY/RNA II-triggered Ehmt2/G9a increase and G9a-controlled pain-related gene decrease in the injured DRG after peripheral nerve injury. Our study will likely identify a previously unknown regulatory mechanism for neuropathic pain. Given that virus- mediated gene therapy has been used in clinical trial, the present study will have a potential clinical application in neuropathic pain management.
|Effective start/end date||4/15/21 → 3/31/22|
- National Institute of Neurological Disorders and Stroke: $490,258.00
- Clinical Neurology