Determining the topology and molecular profiles of nociceptive DRG neurons innervating distal colon and rectum

确定支配远端结肠和直肠的伤害性 DRG 神经元的拓扑结构和分子特征

• 批准号: 10023955
• 负责人: Bin Feng
• 金额: $ 66.96万
• 依托单位: UNIVERSITY OF CONNECTICUT STORRS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-24 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10023955
• 关键词: Action Potentials; Affect; Afferent Neurons; Analgesics; Biological Assay; Cells; Chemicals; Chronic; Clinical; Colon; Colorectal; Development; Devices; Distal; Economic Burden; Electrophysiology (science); Expression Profiling; Fiber; Gene Expression; Glycerol; Goals; Harvest; Hypersensitivity; Image; Individual; Inflammation; Inflammation Mediators; Inflammatory; Ion Channel; Irritable Bowel Syndrome; Knowledge; Location; Mannitol; Mechanics; Mediating; Methods; Molecular Profiling; Mucous Membrane; Mus; Muscle Cramp; Nerve; Neuraxis; Neurons; Neurostimulation procedures of spinal cord tissue; Nociception; Nociceptive Stimulus; Nociceptors; Optics; Organ; Outcomes Research; Pain; Pathway interactions; Patients; Pelvis; Perfusion; Peripheral; Persons; Pharmaceutical Preparations; Pharmacological Treatment; Plant Roots; Play; Population; Preparation; Rectum; Rodent; Role; Sensory; Signal Transduction; Spinal Ganglia; Splanchnic Nerves; Stimulus; Stretching; Subgroup; Sum; Symptoms; Syndrome; Therapeutic; Therapeutic Intervention; Visceral; Visceral pain; chronic pain; colorectal distension; cost; design; imaging platform; nerve supply; neuronal cell body; neuroregulation; next generation; non-drug; novel; painful neuropathy; polyol; relating to nervous system; response; side effect; transcriptome

Project Summary/Abstract Chronic visceral pain is the cardinal symptom of patients with irritable bowel syndrome (IBS) affecting up to 15% of the U.S. population. Efficacious and reliable therapeutic intervention is still unavailable despite the tremendous economic burden imposed by visceral pain. Pharmacological treatments of visceral pain in IBS are largely unsatisfactory with side effects outweighing therapeutic benefits. In contrast, neuromodulation (e.g., spinal cord stimulation) as an alternative to drugs has much fewer side effects. Recent advances in neuromodulation of the dorsal root ganglions (DRG) relieves certain somatic and neuropathic pain. Hence, the DRG appears to be a promising target for next-generation neuromodulatory devices to treat IBS-related visceral pain. However, knowledge is missing regarding the topological distribution and molecular profiles of functionally-characterized DRG neurons innervating the colon and rectum (colorectum), especially colorectal nociceptors. This has significantly hindered the further development of DRG neuromodulation that selectively affects a subset of DRG neurons in treating visceral pain in IBS. We aim to leverage our recent technical advances in optical electrophysiology via Ca2+ imaging and single-cell transcriptome assay of sensory neurons to characterize the topology and molecular profiles of colorectal nociceptors in the thoracolumbar and lumbosacral DRG. Three specific aims are proposed. Specific Aim 1 will quantify the topological distribution of mechano- nociceptors of the colorectum in the thoracolumbar and lumbosacral DRG in control and prolonged colorectal hypersensitivity. Specific Aim 2 will quantify the topological distribution of silent nociceptors of the colorectum in the thoracolumbar and lumbosacral DRG in control and prolonged colorectal hypersensitivity. Specific Aim 3 will define the molecular profiles of mechano- and silent nociceptors of the colorectum in the thoracolumbar and lumbosacral DRG in control and prolonged colorectal hypersensitivity. By establishing a high-throughput optical electrophysiology method, we will be able to functionally characterize a large number (>2000) of colorectal DRG neurons (including nociceptors) and reveal their topological distributions in thoracolumbar and lumbosacral DRG. The single-cell transcriptome analysis on colorectal nociceptors will reveal promising targets for chemical neuromodulation of the DRG. The outcomes of this research will guide the design of next-generation neuromodulatory devices that target DRG for effective management of chronic visceral pain while minimizing off-target side effects.

项目摘要/摘要 慢性内脏疼痛是肠易激综合征（IB）患者的主要症状，影响到 15％的美国人口。有效可靠的治疗干预措施仍然无法 内脏疼痛施加的巨大经济负担。 IBS内脏疼痛的药理学治疗是 副作用大于治疗益处，在很大程度上不满意。相反，神经调节（例如， 脊髓刺激）作为药物的替代品的副作用较少。 背根神经神经（DRG）神经调节的最新进展可缓解某些躯体和 神经性疼痛。因此，DRG似乎是下一代神经调节的有希望的目标 治疗与IBS相关的内脏疼痛的设备。但是，缺少有关拓扑分布的知识 以及功能特征的DRG神经元的分子谱，结肠和直肠（Colorectum），Colorectum）， 特别是结直肠伤害感受器。这极大地阻碍了DRG的进一步发展 在治疗IBS内脏疼痛时，有选择地影响DRG神经元子集的神经调节。我们的目标 利用我们最近通过CA2+成像和单细胞进行光学生理学的技术进步 感官神经元的转录组测定法，以表征结直肠的拓扑结构和分子特征 胸骨和腰椎DRG中的伤害感受器。 提出了三个具体目标。特定的目标1将量化机械的拓扑分布 胸骨骨和腰椎DRG中的结肠癌的伤害感受器在控制和长时间结直肠内 高敏性。特定的目标2将量化Colorectum无声伤害感受器的拓扑分布 胸骨和腰椎DRG在控制和长时间结直肠内超敏反应。具体的目标3将 定义胸木bund骨和静音的伤害感受器的分子曲线 腰椎DRG在对照和长时间结直肠癌过敏。通过建立高通量光学 电生理方法，我们将能够在功能上表征大量（> 2000）的结直肠DRG 神经元（包括伤害感受器），并在胸骨和腰s骨DRG中揭示其拓扑分布。 对结直肠伤害感受器的单细胞转录组分析将揭示有希望的化学目标 DRG的神经调节。这项研究的结果将指导下一代的设计 靶向DRG的神经调节设备可有效管理慢性内脏疼痛，同时最大程度地减少 非目标副作用。