Genetic Control of Nociceptive Sensory Neuron Development and Pain Behavior

伤害性感觉神经元发育和疼痛行为的遗传控制

• 批准号: 7872836
• 负责人: QIUFU MA
• 金额: $ 38.45万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7872836
• 关键词: Ablation; Acute Pain; Address; Afferent Neurons; Behavioral; Biological; Cell Fate Control; Cells; Data; Defect; Development; Disease; Down-Regulation; Embryo; Exhibits; Gene Targeting; Generations; Genetic; Genetic Transcription; Genome; Goals; In Situ Hybridization; Injury; Ion Channel; Knock-in Mouse; Knock-out; Label; Lead; Logic; Malignant Neoplasms; Maps; Mediating; Methods; Modality; Molecular; Mus; Mutant Strains Mice; Neurons; Nociception; Nociceptors; Pain; Pain management; Pattern; Perception; Perinatal; Peripheral; Phenotype; Population; Proteins; Repression; Research; Sensory; Skin; Spinal Cord; Staging; Stimulus; Testing; Time; Work; base; bone; chronic pain; cohort; diabetic; gene repression; human disease; innovation; mutant; nerve supply; neural circuit; neuron development; novel; pain behavior; painful neuropathy; postnatal; prevent; programs; prospective; receptor; response; segregation; therapeutic target; tool; transcription factor

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.

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严重并发症，主要例子是癌症、糖尿病疾病和外伤。 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小鼠胚胎中转录因子的基因组规模表达图谱。 然后，我们使用该图谱，结合靶向基因破坏方法，来识别用于伤害感受/疼痛感觉神经元（伤害感受器）规范的关键蛋白质。 这项工作确定了转录因子 Runxl 作为热痛和神经性疼痛伤害感受器开发的关键药物。 这里描述的研究建立在这项初步工作的基础上。 我们未来五年的研究目标是确定分子机制，使单个转录因子（Runxl）能够控制一大群伤害感受器的形成以及感知疼痛的特定神经回路的组装。 我们有四个具体目标。 目标 1 是确定 Runxl 表达如何控制两种主要伤害感受器亚型（非肽能与肽能）的分离。 目标 2 是解决 Runxl 如何调节伤害性离子通道和受体的表达，目的是了解非肽能伤害性感受器群体中产生巨大多样性的逻辑。 目标 3 侧重于疼痛回路的组装。 在这里，我们想要确定 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。 目标 4 是确定不同的 Runxl 依赖程序如何促进对有害刺激的行为反应。 对于这四个目标中的每一个，我们都有初步数据来得出可检验的假设。 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。 假以时日，这项工作可能会带来一种新的疼痛管理生物学靶点和治疗方法。