Lymphotoxin-Beta Receptor Peripheral Signaling Regulates the Transition to Inflammation and Neuropathy-Induced Chronic Pain

慢性疼痛管理不善导致阿片类药物过度使用，过量相关死亡和心血管，肾脏 和神经系统并发症的流行病为了解决这些问题，有必要阐明 关于控制启动过程的基本机制的知识存在重大差距， 维持慢性疼痛状况。目前的模式意味着组织或神经损伤会触发 保护性免疫反应，应尽快解决其功能完成。如果炎症不是 如果疼痛得到缓解，那么就可能发生从急性疼痛到慢性疼痛的转变。我们建议，关键监管机构的一个 保护性免疫和免疫病理学之间的微妙平衡可能是控制 组织或神经损伤后持续的炎症反应;随后，调节 慢性疼痛的发展。其中一个重要的调节因子是光敏素β受体（LTβR）， 肿瘤坏死因子受体家族成员。本建议的目的是阐明 以及外周LTβR信号如何调节疼痛的起始和维持过程， 炎症和化疗诱导的周围神经病变（CIPN）模型。基于现有 文献和我们的初步数据，我们提出了一个全新的调控机制的启动和 维持炎性和CIPN疼痛，其中外周LTβR信号传导控制这些 通过调节后爪和DRG细胞中的转录和细胞可塑性网络来调节这些过程。 因此，我们的中心假设是，外周LTβR信号控制的过程中启动 和维持炎症和CIPN疼痛，通过控制转录和 细胞可塑性介导外周细胞和感觉神经元之间的交流。我们 假设将通过三个相互关联但独立的目标进行测试。目标1定义了 外周LTβR信号在男性和女性炎症和CIPN疼痛的启动和维持中的作用 雌性老鼠目的2：确定炎症和炎症反应过程中外周LTβR信号转导的细胞基础， CIPN疼痛。目的3检测外周LTβR信号转导对炎症和CIPN诱导的细胞凋亡的影响。 感觉神经元和非神经元转录和细胞可塑性在爪和DRG。拟定研究 创新，因为它描述了概念上新颖的外周调节机制， 慢性疼痛的启动和维持过程，受LTβR的调节。拟议 研究是重要的，因为它（1）促进我们对调节从 急性至慢性疼痛;（2）提供LTβR信号传导拮抗剂作为预防的潜在治疗靶点 CIPN慢性疼痛的完全和持续逆转，以及有效和持久的管理， 炎性疼痛。

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.