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: 7321491
• 负责人: QIUFU MA
• 金额: $ 39.27万
• 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/7321491
• 关键词: Ablation; Acute Pain; Address; Afferent Neurons; Behavior; Behavioral; Biological; Cell Fate Control; Cells; Data; Defect; Development; Disease; Disruption; 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; Range; 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; novel; 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显着并发症，主要例子包括癌症，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吞吐量原位杂交来开发发展小鼠胚胎中转录因子的基因组尺度表达图。 然后，我们将此图与靶向基因破坏方法结合使用，以鉴定关键蛋白质，以指定伤害性/疼痛感官神经元（伤害感受器）。 这项工作导致了转录因子Runxl为热和神经性疼痛的伤害感受器的关键剂。 这里描述的研究基于这项初步工作。 未来五年我们研究的目的是定义允许单个转录因子（RUNXL）控制大量伤害感受器的形成的分子机制，并组装特定的神经回路以感知疼痛。 我们有四个具体的目标。 AIM 1是确定RunXl表达方式如何控制两个主要的伤害感受器亚型的分离，即非肽GTERGIC与肽固醇。 AIM 2是解决RunXl如何调节伤害性离子通道和受体的表达，目的是了解非肽摄影师的非肽型人群中巨大多样性产生的逻辑。 AIM 3专注于止痛电路的组装。 在这里，我们要确定RUNXL如何控制非肽性伤害感受器对特定的外围和中心目标的创新。 AIM 4是确定不同依赖RunXl的程序对有害刺激的行为反应有何作用。 对于这四个目标中的每一个，我们都有初步数据，可导致可检验的假设。 这些假设的预测将通过使用我们已经开发的遗传工具来测试。 在时间的充实中，这项工作可能会导致一种新型的生物学靶标和疼痛管理的治疗方法。