LIGHT and Lymphotoxin induced modulation of trigeminal ganglia sensory neuron excitability

慢性口面疼痛的管理不善在很大程度上导致阿片类药物滥用和阿片类药物相关死亡 以及流行性的心血管、肾脏和神经系统并发症。存在一个临界 关于慢性口面疼痛管理的知识差距，可以通过识别和 积极验证控制其发展和维持的新治疗靶点。我们已经确定 这些目标- LIGHT和光敏素-β（LTβ），并已获得R 01 DE 029187资助， HEAL倡议计划FOA RFA-NS-18-043（标题：安全和安全新目标的发现和验证） 有效的疼痛治疗），以大力验证这些新的治疗目标，控制发展和 维持慢性口面疼痛。这项资助旨在测试中心假设，即针对LIGHT 而LTβ信号通路阻止了慢性疼痛的发展，并抑制了慢性疼痛的维持。 颞下颌肌肉和关节疾病（TMJD）和口腔癌通过外周机制， 免疫、基质和肿瘤细胞以及感觉神经元的可塑性。 本提案的目的是响应“研究补充， 促进健康相关研究的多样性（PA-20-222）"，首先，促进健康相关研究的多样性， 凯伦·林德奎斯特女士是一名博士生，她在生物医学领域的背景不足， 科学，第二，通过测试中心， LIGHT和LTβ调节TMJD诱导特定感觉细胞群兴奋性假说 神经元支配咬肌和颞下颌关节。我们的假设将由两个相关的测试， 独立的目标。目的1识别和表征支配咬肌的感觉神经元类型 和颞下颌关节。目的2定义了LIGHT和LTβ对TMJD诱导的兴奋性的贡献。 支配咬肌和颞下颌关节的三叉神经感觉神经元的不同群体。 这项拟议中的研究将促进健康相关研究的多样性，因为一名博士生来自一个背景 在生物医学科学中代表性不足的人将是这项研究的主要受益者之一。这项研究提供 一个出色的培训机会，因为它几乎包含了多层次研究培训的所有方面 计划，包括多学科的研究方法，数据分析和相关文献， 介绍和发表研究成果，发展研究合作和项目 管理它具有高度的创新性和重要性，因为它将产生关于感官的基本数据。 三叉神经系统中靶组织的神经元类型依赖性。该提案还提出了我们的 了解LIGHT和LTβ调节不同类型感觉神经元兴奋性的机制。

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.