Genetic Control of Nociceptive Sensory Neuron Development and Pain Behavior

描述（由申请人提供）：急性疼痛和慢性疼痛是许多人类疾病的重要并发症，主要例子是癌症，糖尿病疾病和创伤性损伤。在初步研究中，我和我的同事使用高通量原位杂交技术开发了发育中的小鼠胚胎中转录因子的基因组级表达图谱。然后，我们使用该图谱，结合靶向基因破坏方法，确定了指定伤害感觉/疼痛感觉神经元（伤害感受器）的关键蛋白质。这项工作导致鉴定转录因子Runxl在热痛和神经性疼痛的伤害感受器的发展中起关键作用。这里所描述的研究是建立在这一初步工作的基础上的。我们未来五年的研究目标是确定允许单个转录因子（Runxl）控制大量伤害感受器形成和特定神经回路组装的分子机制，以感知疼痛。我们有四个具体目标。目的1是确定Runxl表达如何控制两种主要伤害受体亚型（非肽能型和肽能型）的分离。目的2是解决Runxl如何调节伤害性离子通道和受体的表达，目的是了解在非肽能性伤害感受器群体中产生巨大多样性的逻辑。目的3关注疼痛回路的组装。在这里，我们想确定Runxl如何控制非肽能伤害感受器对特定外周和中枢目标的创新。目的4是确定不同的依赖于runxl的程序如何对有害刺激的行为反应作出贡献。对于这四个目标中的每一个，我们都有初步的数据来得出一个可检验的假设。这些假设的预测将通过使用我们已经开发的一组遗传工具进行测试。随着时间的推移，这项工作可能会为疼痛管理带来新的生物学靶点和治疗方法。

DESCRIPTION (provided by applicant): Acute pain and chronic pain are significant complications in many human diseases, prime examples being cancer, diabetic disorders, and traumatic injury. In preliminary studies, my colleagues and I used high throughput in situ hybridization to develop a genome-scale expression map of transcription factors in developing mouse embryos. We then used this map, in combination with targeted gene disruption methods, to identify key proteins for specification of nociceptive/pain sensory neurons (nociceptors). This work led to identification of the transcription factor Runxl as a pivotal agent in development of nociceptors for thermal and neuropathic pain. The research described here builds upon this preliminary work. The goal of our research over the next five years is to define the molecular mechanisms that allow a single transcription factor (Runxl) to control the formation of a large cohort of nociceptors and the assembly of specific neural circuits for the perception of pain. We have four specific Aims. Aim 1 is to determine how Runxl expression controls the segregation of two major nociceptor subtypes, non-peptidergic versus peptidergic. Aim 2 is to address how Runxl regulates the expression of nociceptive ion channels and receptors, with the goal of understanding the logic underlying the generation of tremendous diversity within the non-peptidergic population of nociceptors. Aim 3 focuses on the assembly of pain circuits. Here we want to determine how Runxl controls the innovation of non-peptidergic nociceptors to specific peripheral and central targets. Aim 4 is to determine how distinct Runxl-dependent programs contribute to behavioral response to noxious stimuli. For each of these four aims, we have preliminary data that leads to a testable hypothesis. The predictions of these hypotheses will be tested by using a panel of genetic tools that we have already developed. In the fullness of time, the work may lead to a novel biological target and therapeutic approach for pain management.