Runxl targets and modulators in manifestation of chronic pain

项目2的长期目标是开发治疗慢性疼痛的新靶点。 具体来说，我们的研究一直集中在那些核心的转录程序，控制 伤害感受器表型和疼痛行为。在上一个融资周期，我们编制了一份 基因组水平分析转录因子在发育中的神经细胞中的表达 系统从这个屏幕上，我们确定了少量的TF表达的疼痛电路。 随后的遗传学研究表明，侏儒类转录因子Runxl是一个关键， 缺乏Runxl的小鼠表现出伤害感受器发育的显著缺陷， 炎性疼痛和神经性疼痛。该项目的实验计划是建立在这些 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性疼痛中的作用：疼痛诱导的疼痛， 通过肿瘤生长或化疗。这一目标是建立在事实上，癌症疼痛是由 炎症性和神经性疼痛成分，Runxl是这两种类型的疼痛所必需的。 慢性疼痛 目的2是确定作为神经性疼痛关键候选物的Runxl靶标。 这一目标是建立在观察到Runxl活性在胚胎阶段，而不是在出生后， 阶段，是神经性疼痛所必需的，这意味着早期Runxl靶点是神经性疼痛后期所必需的。 这种慢性疼痛的发展。 目的3是确定调节成年人Runxl表达的信号通路。 伤害感受器这一目标是建立在这样的发现之上的，即持续的Runxl活动是实现以下目标所必需的： 炎性疼痛。因此，能够消除Runxl表达的化合物可以用作 作为炎症性疼痛治疗的新靶点。 这些目标的研究将通过各种Runxl突变小鼠的可用性来实现 和从“可药用机制核心”（DMC），包括高通量单 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.