LIGHT and Lymphotoxin targeting for the treatment of chronic orofacial pain conditions

口腔慢性疼痛管理不善在很大程度上导致阿片类药物过量使用和过量相关死亡 以及流行比例的心血管、肾脏和神经并发症。为了解决这个问题，它 有必要通过识别和积极验证新的治疗方法来阐明知识中的关键差距 控制慢性口腔面部疼痛的发展和维持的目标。当前的范例意味着 口腔面部疾病，如颞下颌关节和肌肉疾病(TMJD)和口腔癌， 可能会引发免疫系统的不适应和支持持续性炎症的细胞可塑性， 从而影响口腔面部慢性疼痛的发展和维持。灯光(TNFSF14)和 淋巴毒素-β(LT-β)是肿瘤坏死因子超家族的重要成员 控制保护性免疫和免疫病理之间的微妙平衡 炎症性疾病。这一建议的目标是：第一，严格验证地方封锁是否 LIGH和LTβ信号通过LTβ受体(LTβR)或疱疹病毒进入介体(HVEM；TNFRSF14) 在几种TMJD和口腔模型中预防和/或抑制慢性疼痛的发展和/或抑制维持 第二，确定光和LTβ信号诱导的免疫、间质和肿瘤的可塑性 咬肌和舌的细胞，以及三叉神经节(TG)的感觉神经元，导致 口腔面部慢性疼痛。根据现有文献和我们的初步数据，我们的中心假设是 靶向光和LTβ信号将阻止慢性粒细胞白血病的发生和维持 TMJD和口腔癌通过涉及免疫可塑性的外周机制产生疼痛， 间质和肿瘤细胞以及感觉神经元。我们的假设将由三个相关的尚待检验 独立的目标。目的1验证咬肌局部光和LTβ抑制是否能阻止 TMJD模型中慢性疼痛的发展和阻断维持。目标2定义了光的贡献 LT-β对TMJD免疫、间质和神经细胞可塑性的影响。目标3确定光线和 LTβ信号在口腔癌模型慢性疼痛的发生和维持中的作用 舌体细胞可塑性的调控。这项拟议的研究具有创新性，因为它验证了 促进口腔面部慢性疼痛疗法的发展；并提出概念上的新外周 涉及光和LTβ信号的调节机制，控制着细胞的发育和维持 TMJD与口腔癌慢性疼痛。这项拟议的研究具有重要意义，因为它促进了我们对 调控口面部疼痛的发展和维持的机制；并提供靶点和 预防和阻断TMJD和口腔癌慢性疼痛的免疫治疗方法。

Orofacial chronic pain mismanagement substantially contributes to opioid overuse, overdose related deaths and cardiovascular, renal and neurological complications at epidemic proportions. To combat this problem, it is necessary to elucidate a critical gap in knowledge by identifying and vigorously validating novel therapeutic targets controlling the development and maintenance of chronic orofacial pain. The current paradigm implies that orofacial conditions, such as temporomandibular joint and muscle disorders (TMJD) and oral cancer, could trigger maladaptation of the immune system and cell plasticity supporting persistent inflammation, which influences the development and maintenance of orofacial chronic pain. LIGHT (TNFSF14) and Lymphotoxin-beta (LTβ), members of the tumor necrosis factor superfamily, are critical components controlling a delicate balance between protective immunity and immunopathology during chronic inflammatory diseases. The objectives of this proposal are: first, to rigorously validate whether local blockade of LIGHT and LTβ signaling via LTβ receptor (LTβR) or Herpes Virus Entry Mediator (HVEM; TNFRSF14) prevent the development and/or inhibit maintenance of chronic pain in several models of TMJD and oral cancer; and second, to identify LIGHT and LTβ signaling-induced plasticity of immune, stromal and tumor cells in masseter muscle and tongue, as well as of sensory neurons in trigeminal ganglia (TG), leading to orofacial chronic pain. Based on the existing literature and our preliminary data, our central hypothesis is that targeting LIGHT and LTβ signaling will prevent the development and inhibit maintenance of chronic pain produced by TMJD and oral cancer via peripheral mechanisms involving plasticity of immune, stromal and tumor cells as well as sensory neurons. Our hypothesis will be tested by three relevant yet independent aims. Aim 1 validates whether local LIGHT and LTβ inhibition in masseter muscle prevents the development and blocks maintenance of chronic pain in TMJD models. Aim 2 defines contribution of LIGHT and LTβ to immune, stromal and neuronal cell plasticity during TMJD. Aim 3 determines whether LIGHT and LTβ signaling contribute to the development and maintenance of chronic pain in oral cancer models via regulation of cell plasticity in tongue. The proposed study is innovative because it validates novel targets to facilitate the development of orofacial chronic pain therapeutics; and proposes conceptually novel peripheral regulatory mechanisms involving LIGHT and LTβ signaling that control the development and maintenance of TMJD and oral cancer chronic pain. The proposed research is significant as it advances our understanding of mechanisms regulating the development and maintenance of orofacial pain; and offers targets and an immunotherapeutic approach for preventing and blocking chronic pain during TMJD and oral cancer.