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: 8489281
• 负责人: QIUFU MA
• 金额: $ 39.84万
• 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 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8489281
• 关键词: Acute; Address; Affect; Afferent Neurons; Alleles; Arthralgia; Biological Assay; Bone Pain; Caliber; Chronic; Clinic; Complex; Conflict (Psychology); Cutaneous; Defect; Development; Disinhibition; Epidermis; Foundations; Free Nerve Ending; Funding; Genes; Genetic; Genetic Programming; Glutamate Transporter; Goals; Hair follicle structure; Homeobox Genes; Inflammation; Injury; Joints; Knock-out; Knockout Mice; Knowledge; Lesion; Maps; Measures; Mechanics; Mechanoreceptors; Mediating; Merkel Cells; Modality; Molecular; Mus; Muscle; Myalgia; Nerve; Neurites; Neurons; Nociception; Nociceptors; Organ; Pain; Pain Disorder; Pathway interactions; Perception; Physiological; Play; Population; Role; Sensory; Series; Skin; Spinal Ganglia; Stimulus; Synapses; Temperature; Testing; Thinking; Tissues; Variant; Visceral; Visceral pain; Work; base; bone; chronic pain; clinically relevant; clinically significant; insight; mechanical allodynia; neuron development; pain behavior; painful neuropathy; programs; transcription factor

DESCRIPTION (provided by applicant): The long-range goal is to identify the genetic programs controlling the formations of specific sensory pathways and to gain insight into the molecular and cellular basis of pain perception. In this renewal application, we try to address two major knowledge gaps. First, most clinically relevant pain is derived from deep tissues, such as muscle, joint, bone, and visceral organs. Despite this clinical significance, the molecular and cellular basis of "deep" pain is still poorly understood, which is in stark contrast to the tremendous progress made in the past decades in understanding cutaneous pain. In Aim 1 studies, we will establish a molecular map for sensory neurons innervating distinct deep tissues. We will also determine if Meis1 represents the first transcription factor that controls the development of deep tissue sensory neurons. Second, the cellular basis of mechanical allodynia (pain evoked by innocuous mechanical stimuli), a hallmark for most, if not all, chronic pain disorders, needs further clarification. In case of neuropathic pain, it was proposed that central disinhibition will allow low threshold myelinated A¿ mechanoreceptors to directly activate the pain pathways. However, a recent study proposed that unmyelinated low threshold c- mechanoreceptors, marked by the expression of the vesticular glutamate transporter VGLUT3, may play an essential role in the readout of the mechanical allodynia. Our preliminary genetic fate-mapping studies show that VGLUT3 lineage neurons are in fact composed of both 1) unmyelinated c-mechanoreceptors that form free nerve endings in the skin epidermis and lanceolate endings around hair follicles, and 2) myelinated m-mechanoreceptors that form the Merkel-cell neurite complex. In Aim 2, we will determine if Zfp521, a transcription factor expressed exclusively in VGLUT3 lineage c-mechanoreceptor, is necessary for the development of these c-mechnaoreceptors. We will also determine if mechanical allodynia is differentially affected in mice that will have a selective developmental defect in VGLUT3 lineage c- mechanoreceptors or a defect in the VGLUT3-expressing Merkel cell-neurite complex. Together, these studies will gain insight into 1) the genetic programs that control the formation of the deep tissue pain pathways, and 2) the identities of low threshold mechanoreceptors mediating the readout of mechanical allodynia.

描述（由申请人提供）：长期目标是确定控制特定感觉通路形成的遗传程序，并深入了解疼痛感知的分子和细胞基础。在此续订应用程序中，我们尝试解决两个主要的知识差距。 首先，大多数临床相关疼痛源自深层组织，例如肌肉、关节、骨骼和内脏器官。尽管具有这种临床意义，但分子 对“深层”疼痛的细胞基础仍然知之甚少，这与过去几十年在理解皮肤疼痛方面取得的巨大进展形成鲜明对比。在目标 1 研究中，我们将为支配不同深层组织的感觉神经元建立分子图谱。我们还将确定 Meis1 是否代表控制深部组织感觉神经元发育的第一个转录因子。 其次，机械异常性疼痛（由无害的机械刺激引起的疼痛）的细胞基础是大多数（如果不是全部）慢性疼痛疾病的标志，需要进一步澄清。在神经病理性疼痛的情况下，有人提出中枢去抑制将允许低阈值有髓鞘 A 机械感受器直接激活疼痛通路。然而，最近的一项研究提出，以前庭谷氨酸转运蛋白 VGLUT3 的表达为标志的无髓鞘低阈值 c-机械感受器可能在机械异常性疼痛的读出中发挥重要作用。我们的初步遗传命运图谱研究表明，VGLUT3 谱系神经元实际上由以下两种成分组成：1) 无髓鞘 c 机械感受器，在皮肤表皮和毛囊周围形成游离神经末梢和披针形末端；2) 有髓鞘 m 机械感受器，形成默克尔细胞神经突复合体。在目标 2 中，我们将确定 Zfp521（一种仅在 VGLUT3 谱系 c-机械感受器中表达的转录因子）对于这些 c-机械感受器的发育是否是必需的。我们还将确定机械性异常性疼痛在具有 VGLUT3 谱系 c-机械感受器选择性发育缺陷或表达 VGLUT3 的默克尔细胞-神经突复合体中存在缺陷的小鼠中是否受到不同程度的影响。 总之，这些研究将深入了解 1）控制深部组织疼痛通路形成的遗传程序，以及 2）介导机械异常性疼痛读数的低阈值机械感受器的身份。