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

LIGHT 和淋巴毒素靶向治疗慢性口面部疼痛

• 批准号: 10221292
• 负责人: ARMEN N AKOPIAN
• 金额: $ 23.1万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-20 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10221292
• 关键词: Acute; Address; Afferent Neurons; Age; Autoimmune Process; Body Temperature; Cancer Model; Cardiovascular system; Cell Line; Cells; Cessation of life; Chronic; Chronic Cancer Pain; Complex; Consensus; Constipation; Data; Development; Disease model; Epidemic; Equilibrium; Female; Fiber; Flow Cytometry; Gene Expression; Gene Targeting; Genes; Goals; Health; Herpesviridae; Human; Immune; Immune System Diseases; Immune system; Immunity; Immunohistochemistry; Immunologics; Immunotherapeutic agent; Inflammation; Injections; Intervention; Kidney; Knowledge; Lead; Ligands; Literature; Maintenance; Malignant Neoplasms; Masseter Muscle; Mediating; Mediator of activation protein; Modeling; Mus; Myeloid Cells; Nerve; Neuroglia; Neurologic; Neurons; Opioid; Opioid Analgesics; Orofacial Pain; Overdose; Pain; Pain management; Pathway interactions; Peripheral; Pharmaceutical Preparations; Pharmacology; Prevention; Regulation; Research; Sensory; Signal Transduction; Stromal Cells; Stromal Neoplasm; Structure of trigeminal ganglion; TNF gene; Temporomandibular Joint Disorders; Testing; Therapeutic; Tongue; Translating; Treatment Efficacy; Tumor Necrosis Factor Receptor; Tumor Necrosis Factor-Beta; Validation; Xenograft Model; addiction; aged; base; cancer cell; chronic inflammatory disease; chronic pain; chronic painful condition; clinically relevant; combat; defined contribution; drug efficacy; herpesvirus entry mediator; high voltage electron microscopy; human subject; immunopathology; innovation; local drug delivery; lymphotoxin beta; lymphotoxin beta receptor; malignant mouth neoplasm; mechanical allodynia; member; mouth squamous cell carcinoma; neoplastic cell; neuronal excitability; new therapeutic target; next generation; novel; novel therapeutics; opioid epidemic; opioid overuse; orofacial; orofacial development; pain model; pain relief; prevent; receptor; receptor expression; sex; side effect; therapeutic target; transcriptome sequencing

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.

口面部慢性疼痛管理不善在很大程度上导致阿片类药物过度使用，过量相关死亡 以及心血管、肾脏和神经系统并发症的流行。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的关键差距 控制慢性口面部疼痛的发展和维持的目标。当前的模式意味着 口面部疾病，如颞下颌关节和肌肉疾病（TMJD）和口腔癌， 可能引发免疫系统和细胞可塑性的适应不良，支持持续性炎症， 其影响口面部慢性疼痛的发展和维持。LIGHT（TNFSF 14）和 肿瘤坏死因子超家族成员β-光氧合素（LTβ）是肿瘤坏死因子的重要组成部分 在慢性疾病期间控制保护性免疫和免疫病理学之间的微妙平衡， 炎症性疾病。该提案的目标是：第一，严格验证局部封锁是否 LIGHT和LTβ信号通过LTβ受体（LTβR）或疱疹病毒进入介体（HVEM; TNFRSF 14） 在几种TMJD和口腔炎模型中预防慢性疼痛的发展和/或抑制慢性疼痛的维持， 第二，鉴定LIGHT和LTβ信号诱导的免疫、间质和肿瘤的可塑性 咬肌和舌中的神经元，以及三叉神经节（TG）中的感觉神经元，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LIGHT和LTβ信号传导将阻止慢性炎症的发展和抑制慢性炎症的维持。 TMJD和口腔癌通过涉及免疫可塑性的外周机制产生的疼痛， 基质细胞和肿瘤细胞以及感觉神经元。我们的假设将由三个相关的测试， 独立的目标。目的1验证咬肌中局部LIGHT和LTβ抑制是否阻止 在TMJD模型中抑制慢性疼痛的发展和阻断慢性疼痛的维持。目标2定义了光的贡献 LTβ对TMJD时免疫、间质和神经细胞可塑性的影响。目标3确定光和 LTβ信号通过介导的途径促进口腔癌模型中慢性疼痛的发展和维持 调节舌细胞的可塑性。这项研究是创新的，因为它验证了新的目标， 促进口面部慢性疼痛治疗的发展;并提出了概念上新颖的外周 涉及LIGHT和LTβ信号传导的调节机制，控制着 TMJD和口腔癌慢性疼痛。这项拟议的研究意义重大，因为它促进了我们的理解 调节口面疼痛的发展和维持的机制，并提供了目标和 预防和阻断TMJD和口腔癌期间慢性疼痛的免疫学方法。