Runxl targets and modulators in manifestation of chronic pain

Dana-Farber Cancer Inst, Boston MA

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Abstract

The long-term goal of Project 2 is to develop new targets for the treatment of chronic pain. Specifically, our research has been focusing on those core transcriptional programs that control nociceptor phenotypes and pain behaviors. In the previous funding cycle, we have compiled a genome-scale analysis of the expression of transcription factors (TFs) in the developing nervous system. From this screen, we identified a small number of TFs expressed in the pain circuitry. Subsequent genetic studies demonstrated that the runt class transcripfion factor Runxl is a key regulator of nociceptor development, and mice lacking Runxl exhibit a marked deficit in inflammatory pain and neuropathic pain. The experimental plan of this project is built on these preliminary studies, and we have three specific aims. Aim 1 is to determine the roles of Runxl in controlling two types of cancer pain: pain induced by tumor growth or by chemotherapy. This aim is built on the facts that cancer pain is composed of both inflammatory and neuropathic pain components, and Runxl is required for these two types of chronic pain. Aim 2 is to determine Runxl targets that serve as candidates critical for neuropathic pain. This aim is built on the observation that Runxl activity at embryonic stages, rather than at postnatal stages, is required for neuropathic pain, implying that early Runxl targets are later required for the development of this type of chronic pain. Aim 3 is to determine signaling pathways that modulate Runxl expression in adult nociceptors. This aim is built on the finding that persistent Runxl activity is required for inflammatory pain. Accordingly, compounds capable of extinguishing Runxl expression may serve as new targets for inflammatory pain treatment. The studies of these aims will be enabled by the availability of various Runxl mutant mice and from the "Druggable Mechanisms Core" (the DMC), including high throughput single molecule DNA sequencing and bioinformatics analyses.