PUFA metabolism for prevention and treatment of TMD pain: an interdisciplinary, translational approach.

omega-3膳食多不饱和脂肪酸（n-3 PUFA）的有效衍生物包括专门的 具有抗炎、促消退、镇痛和抗焦虑作用的促消退脂质介质（SPM） 特性.因此，PUFA代谢代表了疼痛转化研究的理想焦点。 颞下颌关节紊乱病（TMD）是一种多因素疾病，通常表现为关节痛和 肌痛，并且其通常与一系列共病状况一起呈现。作为证据，我们的观察 研究表明低水平的循环n-3 PUFA与痛觉过敏，心理困扰， TMD和其他四种共病的疼痛强度增加，临床TMD的可能性更大。 二十年来，我们的研究团队通过基础和临床实践， 临床研究我们现在扩大了我们的学科范围，在基础科学，功能磁 共振成像和机器学习数据分析。我们的最终目标是创造一种新颖的、非侵入性的 预防和管理TMD及其相关并发症的干预措施为解决RFA-DE-23-014， 我们将计划一个以患者为中心的转化研究合作项目（TMD IMPACT）， 传统的计划项目设计，以管理我们的研究和协调研究成果在国家 TMD影响协作。在为期一年的R34规划阶段，我们将完成四个具体目标： 1)制定方案并进行试点研究，为使用小鼠模型进行基础研究做准备， 在SPM受体转基因/敲除小鼠中激发TMD样疼痛，以确定通过 其中n-3 PUFA代谢物介导TMD中的疼痛过程。 2)计划进行一项随机临床试验，评估添加SPM的n-3 PUFA膳食补充剂， 临床TMD疼痛的主要结局、TMD合并症的次要结局和疼痛生物标志物 中央和外围的过程。 3)获得对现有数据进行流行病学分析的批准，以估计TMD患病率，其成本， 社会及其与未充分研究的种族多样的西班牙裔人群中的循环PUFA的关联。 4)分析现有的博士和博士后培训计划的景观，以开发跨学科的 TMD研究人员的培训计划，强调生物医学研究的严谨性和可重复性。 我们在规划和准备合作协议的研究文件方面有着成功的记录， TMD研究。我们的计划将由团队科学顾问、监管/FDA专家和 来自美国科学院CTSA计划的包容性科学专家。社区参与专家将优化 我们与患者倡导者和卫生专业人员的沟通，以告知我们的研究重点。我们的重点 对n-3多不饱和脂肪酸及其代谢物的研究为跨学科研究和培训提供了令人信服的动力 并最终使新的转化科学造福于疼痛的TMD患者。

The potent derivatives of omega-3 dietary polyunsaturated fatty acids (n-3 PUFAs) include specialized proresolving lipid mediators (SPMs) that have anti-inflammatory, proresolving, analgesic, and anxiolytic properties. PUFA metabolism therefore represents an ideal focus for translational research into painful temporomandibular disorder (TMD), a multifactorial condition that typically manifests as both arthralgia and myalgia, and which usually presents with an array of comorbid conditions. As evidence, our observational studies show that low levels of circulating n-3 PUFAs are associated with hyperalgesia, psychological distress, increased pain intensity from TMD and four other comorbid conditions, and greater odds of clinical TMD. For two decades, our research team has translated knowledge of TMD and its treatment through basic and clinical research. We now broaden our disciplinary scope with expertise in basic science, functional magnetic resonance imaging and machine learning data analysis. Our ultimate goal is to create novel, non-invasive interventions for prevention and management of TMD and its related comorbidity. To address RFA-DE-23-014, we will plan a Collaborative for IMproving PAtient-Centered Translational Research (TMD IMPACT), creating a traditional program-project design to manage our studies and harmonize research outputs within the national TMD IMPACT Collaborative. During the one-year R34 planning phase, we will complete four specific aims: 1) Develop protocols and conduct a pilot study to prepare for basic research using a murine model that elicits TMD-like pain in SPM receptor transgenic/knockout mice to identify mechanisms and pathways through which n-3 PUFA metabolites mediate pain-processes in TMD. 2) Plan a randomized clinical trial of an n-3 PUFA dietary supplement enhanced with SPMs to evaluate primary outcomes of clinical TMD pain, secondary outcomes of TMD comorbidities, and biomarkers of pain processes, both central and peripheral. 3) Obtain approvals for epidemiologic analysis of existing data to estimate TMD prevalence, its costs to society and its associations with circulating PUFAs in understudied ethnically diverse Hispanic populations. 4) Analyze the landscape of existing PhD and postdoctoral training programs to develop an interdisciplinary training program for TMD researchers that emphasize rigor and reproducibility in biomedical research. We have a successful track record in planning and preparing study documents for cooperative agreements in TMD research. Our planning will be facilitated by team science consultants, regulatory/FDA experts, and inclusive science specialists drawn from UNC’s CTSA program. Community engagement experts will optimize our communication with patient advocates and health professionals to inform our research priorities. Our focus on n-3 PUFAs and their metabolites provides the compelling impetus for interdisciplinary research and training and, ultimately, for new translational science to benefit patients with painful TMD.