LIGHT and Lymphotoxin induced modulation of trigeminal ganglia sensory neuron excitability

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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.