LIGHT and Lymphotoxin induced modulation of trigeminal ganglia sensory neuron excitability

光和淋巴毒素诱导三叉神经节感觉神经元兴奋性的调节

• 批准号: 10177229
• 负责人: ARMEN N AKOPIAN
• 金额: $ 19.72万
• 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: 2020-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10177229
• 关键词: Action Potentials; Address; Affect; Afferent Neurons; Award; Back; Basic Science; Capsaicin; Cardiovascular system; Cell Separation; Cells; Cessation of life; Characteristics; Chronic; Collaborations; Complement; Data; Data Analyses; Data Correlations; Dependence; Development; Electrophysiology (science); Epidemic; Female; Funding; Funding Opportunities; Genetic Transcription; Grant; Health; Immune; Individual; Kidney; Knowledge; Label; Ligands; Literature; Maintenance; Masseter Muscle; Methods; Mus; Neurologic; Neurons; Opioid; Orofacial Pain; Pain; Pain Disorder; Pain management; Parents; Pattern; Peripheral; Pharmaceutical Preparations; Physiological; Population; Prevention; Property; Publications; Reporter; Research; Research Training; Science; Serotonin; Signal Transduction; Spinal Ganglia; Stromal Cells; Structure of trigeminal ganglion; Techniques; Temporomandibular Joint; Temporomandibular Joint Disorders; Testing; Tissues; Training; Training Programs; Treatment Efficacy; Trigeminal System; Tumor Necrosis Factor Receptor; Tumor Necrosis Factor-Beta; Underrepresented Students; Validation; Women' s Group; base; beneficiary; chronic pain; defined contribution; doctoral student; experimental study; in vivo; innovation; interdisciplinary approach; lymphotoxin beta; male; malignant mouth neoplasm; member; neoplastic cell; new therapeutic target; non-opioid analgesic; novel; opioid epidemic; opioid misuse; opioid mortality; pain relief; parent grant; prevent; programs; receptor; research and development; response; single cell sequencing; training opportunity; transcriptomics

Mismanagement of chronic orofacial pain substantially contributes to opioid misuse and opioid related deaths as well as to cardiovascular, renal and neurological complications at epidemic proportions. There is a critical gap in knowledge about the management of chronic orofacial pain which can be addressed by identifying and vigorously validating novel therapeutic targets controlling its development and maintenance. We have identified such targets - LIGHT and Lymphotoxin-beta (LTβ), and have been awarded a R01 DE029187 grant within the HEAL Initiative program FOA RFA-NS-18-043 (title: Discovery and Validation of Novel Targets for Safe and Effective Pain Treatment) to vigorously validate these novel therapeutic targets in control of development and maintenance of chronic orofacial pain. This parent grant aims to test central hypothesis that targeting LIGHT and LTβ signaling prevents the development of and inhibits maintenance of chronic pain produced by temporomandibular muscle and joint disorders (TMJD) and oral cancer via peripheral mechanisms involving plasticity of immune, stromal and tumor cells as well as sensory neurons. The objectives of this current proposal, which is submitted in response to opportunity “Research Supplement to Promote Diversity in Health-Related Research (PA-20-222)”, are: first, to promote diversity in health-related research by training Ms. Karen Lindquist, a PhD student from a background underrepresented in bio-medical sciences, and second, to enhance a basic science aspect of the parent application by testing the central hypothesis that LIGHT and LTβ modulate TMJD-induced excitability of specific populations of sensory neurons innervating the masseter muscle and the TMJ. Our hypothesis will be tested by two related yet independent aims. Aim 1 identifies and characterizes sensory neuron types innervating the masseter muscle and the TMJ in naïve mice. Aim 2 defines the contribution of LIGHT and LTβ to TMJD-induced excitability of different groups of trigeminal sensory neurons innervating the masseter muscle and the TMJ. The proposed study will promote diversity in health-related research, since a PhD student from a background underrepresented in bio-medical sciences will be one of main beneficiaries of this study. This study provides an outstanding training opportunity, since it contains almost all aspects of a multi-level research training program, including a multi-disciplinary approach to research, data analysis and correlation to the literature, presentation and publication of research findings, development of research collaborations and project management. It is highly innovative and significant because it will generate fundamental data on sensory neuron type-dependency from target tissues in the trigeminal system. The proposal also advances our understanding of the mechanisms regulating excitability of different sensory neuron types by LIGHT and LTβ.

慢性口面疼痛的管理不善大大导致滥用和与OOID相关的死亡 以及在流行比例处的心血管，肾脏和神经系统并发症。有关键 关于管理慢性类似疼痛管理的知识差距，可以通过识别和 大力验证了控制其开发和维护的新型热目标。我们已经确定了 这样的靶标 - 光和淋巴毒素-BETA（LTβ），并已获得R01 DE029187授予 治愈倡议计划FOA RFA-NS-18-043（标题：安全和安全目标的发现和验证 有效的疼痛治疗），以控制发展和 维持慢性口面疼痛。该父母赠款旨在检验靶向光的中心假设 和LTβ信号传导可防止并抑制由 颞下颌肌肉和关节疾病（TMJD）和口腔癌通过涉及的外围机制 免疫学，基质和肿瘤细胞以及感觉神经元的可塑性。 该当前建议的目标是为了响应机会的“研究补充 促进与健康相关研究的多样性（PA-​​20-222）”，是：首先，促进与健康相关的多样性 培训Karen Lindquist女士的研究，来自背景的博士学位学生在生物医学领域的代表性不足 科学，其次是通过测试中心来增强父母应用的基础科学方面 假设光和LTβ调节TMJD引起的特定感觉群体的刺激性 神经元支配咬合肌肉和TMJ。我们的假设将通过两个相关的测试 独立目标。 AIM 1识别并表征了感官神经元类型的支配kasseter肌肉 和天真小鼠的TMJ。 AIM 2定义了光和LTβ对TMJD引起的兴奋的贡献 不同组的三叉神经元神经支配了kasseter肌肉和TMJ。 拟议的研究将促进与健康相关的研究的多样性，因为来自背景的博士生 生物医学中的代表性不足将是本研究的主要受益者之一。这项研究提供 出色的培训机会，因为它包含了多层次研究培训的几乎所有方面 计划，包括用于研究，数据分析和与文献相关的多学科方法， 研究结果的介绍和发布，研究合作的发展和项目 管理。它具有高度创新性和意义，因为它将生成有关感官的基本数据 三叉神经系统中目标时间的神经元类型依赖性。该提议也推动了我们的 了解通过光和LTβ来理解不同感觉神经元类型的令人兴奋的机制。