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: 8889507
• 负责人: QIUFU MA
• 金额: $ 41.5万
• 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 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8889507
• 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。在这个更新应用程序中，我们试图解决两个主要的知识差距。 首先，大多数临床相关疼痛来自深部组织，如肌肉、关节、骨骼和内脏器官。尽管有这种临床意义， 然而，对“深部”疼痛的细胞基础仍然知之甚少，这与过去几十年来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的研究中，我们将建立一个分子地图的感觉神经元支配不同的深部组织。我们还将确定Meis 1是否代表控制深层组织感觉神经元发育的第一个转录因子。 第二，机械性异常性疼痛（由无害的机械刺激引起的疼痛）的细胞基础需要进一步澄清，这是大多数（如果不是全部的话）慢性疼痛疾病的标志。在神经性疼痛的情况下，有人提出，中枢去抑制将允许低阈值的有髓鞘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，无髓鞘低阈值c-机械感受器，其标志是囊泡谷氨酸转运蛋白VGLUT 3的表达，可能在机械异常性疼痛的读出中起重要作用。我们的初步遗传命运作图研究表明，VGLUT 3谱系神经元实际上由以下两种组成：1）在皮肤表皮中形成游离神经末梢和毛囊周围的披针形末梢的无髓鞘c-机械感受器，和2）形成Merkel细胞神经突复合体的有髓鞘m-机械感受器。在目的2中，我们将确定Zfp 521，一种只在VGLUT 3谱系c-机械受体中表达的转录因子，是否是这些c-机械受体发育所必需的。我们还将确定在VGLUT 3谱系c-机械感受器中具有选择性发育缺陷或表达VGLUT 3的默克尔细胞-神经突复合体中具有缺陷的小鼠中机械性异常性疼痛是否受到差异性影响。 总之，这些研究将深入了解1）控制深层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出的低阈值机械感受器的身份。