Lymphotoxin-beta receptor peripheral signaling regulates the transition to inflammation and neuropathy-induced chronic pain

淋巴毒素-β受体外周信号传导调节向炎症和神经病变引起的慢性疼痛的转变

• 批准号: 10164882
• 负责人: ARMEN N AKOPIAN
• 金额: $ 49.1万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10164882
• 关键词: Acute; Acute Pain; Address; Afferent Neurons; Age; Agonist; Cardiovascular system; Cell Separation; Cells; Cessation of life; Chemotherapy-induced peripheral neuropathy; Communication; Complex; Cutaneous; Data; Development; Electrophysiology (science); Epidemic; Equilibrium; Female; Fiber; Fibrinogen; Freund' s Adjuvant; Genes; Genetic Transcription; Goals; Health; Hypersensitivity; Immune; Immune response; Immunity; Immunotherapeutic agent; Inflammation; Inflammatory; Inflammatory Response; Ipsilateral; Kidney; Knockout Mice; Knowledge; Lead; Ligands; Literature; Maintenance; Measures; Mechanics; Mediating; Modeling; Mus; Neurologic; Neurons; Neuropathy; Nociception; Opioid Analgesics; Overdose; PTPRC gene; Paclitaxel; Pain; Pain management; Pathway interactions; Patients; Pattern; Peripheral; Peripheral Nervous System Diseases; Persistent pain; Population; Prevention; Prevention approach; Process; Receptor Activation; Receptor Signaling; Research; Resolution; Sensory; Signal Transduction; Stratum Basale; Testing; Tissues; Translating; Tumor Necrosis Factor Receptor; Tumor Necrosis Factor-Beta; Up-Regulation; Work; base; cell type; chronic pain; chronic painful condition; combat; conditional knockout; defined contribution; epidermis cell; human subject; immunopathology; inflammatory pain; innovation; lymphotoxin beta receptor; male; mechanical allodynia; member; nerve damage; novel; novel therapeutics; opioid epidemic; opioid overdose; opioid overuse; pain chronification; pain model; prevent; sex; side effect; therapeutic target; therapeutically effective; trafficking; transcriptome sequencing; transcriptomics

Chronic pain mismanagement has led to opioid overuse, overdose related deaths and cardiovascular, renal and neurological complications at epidemic proportions. To combat these problems, it is essential to elucidate critical gaps in knowledge pertaining to the underlying mechanisms controlling the processes of initiation and maintenance of chronic pain conditions. The current paradigm implies that tissue or nerve damage triggers protective immune response that should be resolved as soon as its function is fulfilled. If inflammation is not resolved, then transition from the acute to chronic pain could occur. We propose that critical regulators of a delicate balance between protective immunity and immunopathology could be good candidates for controlling a sustained inflammatory response after tissue or nerve damage; and subsequently, regulating the process of development of chronic pain. One of such critical regulators is lymphotoxin-beta receptor (LTβR), a member of the tumor necrosis factor receptor family. The objective of this proposal is to elucidate whether and how peripheral LTβR signaling regulates the process of the initiation and maintenance of pain in inflammatory and chemotherapy-induced peripheral neuropathy (CIPN) models. Based on the existing literature and our preliminary data, we propose an entirely novel regulatory mechanism for the initiation and maintenance of inflammatory as well as CIPN pain wherein peripheral LTβR signaling controls these processes by regulating the network of transcriptional and cellular plasticity in hindpaw and DRG cells. Accordingly, our central hypothesis is that peripheral LTβR signaling controls the processes of initiation and maintenance of inflammatory and CIPN pain via governing the network of transcriptional and cellular plasticity mediating communication between peripheral cells and sensory neurons. Our hypothesis will be tested by three interconnected yet independent aims. Aim 1 defines the impact of peripheral LTβR signaling on the initiation and maintenance of inflammatory and CIPN pain in male and female mice. Aim 2 determines the cellular basis of LTβR signaling at the periphery during inflammatory and CIPN pain. Aim 3 examines the impact of peripheral LTβR signaling on inflammation- and CIPN-induced sensory neuronal and non-neuronal transcriptional and cell plasticity in paw and DRG. The proposed study is innovative because it describes conceptually novel peripheral regulatory mechanism controlling the processes of initiation and maintenance of chronic pain, which are regulated by LTβR. The proposed research is significant as it (1) advances our understanding of mechanisms regulating the transition from acute to chronic pain; and (2) offers LTβR signaling antagonists as potential therapeutic targets for prevention and full and sustained reversal of CIPN chronic pain, as well as effective and long-lasting management of inflammatory pain.

慢性疼痛失踪导致阿片类药物过量使用，与药物过量相关的死亡和心血管，肾脏 和流行比例的神经系统并发症。要解决这些问题，必须阐明 了解与控制启动过程和的基本机制有关的关键差距 维持慢性疼痛状况。当前的范式意味着组织或神经损伤触发 保护性免疫反应应在实现其功能后立即解决。如果不是炎症 解决，然后可能会从急性到慢性疼痛过渡。我们提出了一个关键的监管机构 受保护的免疫和免疫病理学之间的微妙平衡可能是控制的好候选者 组织或神经损伤后持续的炎症反应；随后，控制了 慢性疼痛的发展。这样的关键调节剂之一是淋巴毒素-beta受体（LTβR），A 肿瘤坏死因子受体家族的成员。该提议的目的是阐明是否 以及外围LTβR信号传导如何调节主动和维持疼痛的过程 炎症和化学疗法诱导的周围神经病（CIPN）模型。基于现有的 文学和我们的初步数据，我们提出了一种全新的主动性调节机制， 维持炎症和CIPN疼痛，其中外周LTβR信号控制这些 通过计算后爪和DRG细胞中的转录和细胞可塑性网络来进行过程。 据此，我们的中心假设是外围LTβR信号控制起始过程 以及通过管理转录网络和 细胞塑性介导外周细胞与感觉神经元之间的通信。我们的 假设将通过三个相互连接但独立的目标进行检验。 AIM 1定义了 外周LTβR信号传导关于男性炎症和CIPN疼痛的主动性和维持 雌鼠。 AIM 2确定炎症期间LTβR信号传导的细胞基础 CIPN疼痛。 AIM 3检查了外围LTβR信号传导对注射和CIPN诱导的影响 爪和DRG中的感觉神经元和非神经元转录和细胞可塑性。拟议的研究是 创新性，因为它描述了控制概念的新外围调节机制 慢性疼痛的主动性和维持的过程受到LTβR的调节。提议 研究很重要（1）提高了我们对调节过渡机制的理解 急性到慢性疼痛； （2）提供LTβR信号拮抗剂作为预防的潜在治疗靶标 以及CIPN慢性疼痛的充分和持续的逆转，以及有效的持久管理 炎症性疼痛。