Runxl targets and modulators in manifestation of chronic pain

项目2的长期目标是为慢性疼痛的治疗开发新的目标。 具体地说，我们的研究一直集中在那些控制 伤害性感受器表型和疼痛行为。在上一个资金周期中，我们编制了一份 转录因子在发育神经中表达的基因组水平分析 系统。从这个屏幕上，我们确定了在痛觉环路中表达的少量TF。 随后的遗传学研究表明，矮小类转录因子Runx1是一个关键 伤害性感受器发育的调节因子和缺乏Runxl的小鼠表现出明显的 炎症性疼痛和神经病理性疼痛。该项目的实验计划是建立在这些基础上的 初步研究，我们有三个具体目标。 目的1是确定Runxl在控制两种类型的癌痛中的作用：引起的疼痛 通过肿瘤生长或化疗。这一目标是建立在癌症疼痛由以下几个因素组成的事实之上的 炎性和神经性疼痛成分，这两种类型的疼痛都需要Runxl 慢性疼痛。 目标2是确定作为神经病理性疼痛关键候选靶点的Runx1。 这个目的是建立在观察到Runx1在胚胎阶段而不是在出生后活动的基础上的 阶段，是神经病理性疼痛所必需的，这意味着早期Runx1靶点在以后需要用于 这种类型的慢性疼痛的发展。 目标3是确定调节成人Runx1表达的信号通路 痛觉感受器。这个目标建立在一个发现的基础上，即需要持久化的Runxl活动 炎症性疼痛。因此，能够消除Runx1表达的化合物可以用于 作为炎症性疼痛治疗的新靶点。 随着各种Runx1突变小鼠的出现，对这些目标的研究将成为可能 并从“可药物机制核心”(DMC)，包括高通量单核 分子DNA测序和生物信息学分析。

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.