Local and Systemic Multi-Omics of TMJ Disorders

项目总结/摘要 颞下颌关节紊乱病（TMD）是一系列疼痛性疾病，约有5至10岁的人患有这种疾病。 占美国人口的10%，每年的医疗费用约为40亿美元。退行性疾病， 内部紊乱，包括椎间盘移位和低/高活动度，以及关节痛 颞下颌关节（TMJ），其一起被称为TMJ病症（TMJD），在 很多人都患有TMD。目前还没有明确的病因病理诊断， 非特异性的，并且很大程度上是姑息性的。虽然TMJD的一个子集单独发生，但很大一部分是 与合并症如头痛和/或纤维肌痛相关。这两个不同的患者队列 再加上TMJD对育龄妇女的特殊偏好，而不是晚发性TMJD。 其他关节中的类似病症指出了系统和局部因素的独特而复杂的相互作用。作为 这样，在局部和系统水平上的多组学特征和细胞网络将促进特定诊断 以及这些组群中的每一个之间和之内的患者的临床上有意义的分层。目前有一个 在连接分子多组学特征和细胞网络/相互作用方面存在大量空白， 临床疾病亚型、发病机制、进展和严重程度。我们的长期目标是确定当地 以及来自TMJD亚型谱的系统性单细胞和生物流体多组学分子谱， 描述具有深层组学特征的临床表型与细胞网络之间关系的严重性 这将为合理和精确的治疗、诊断和预防开辟新的方向。我们预计 这种多组学分析与病例对照和纵向临床和成像数据相结合， 提供与特定疾病亚型相关的新型分子特征和网络的重要见解 /严重性和细胞亚群之间的相互作用在维持或减轻疾病进展中的作用。 这些目标将通过两个基于里程碑的阶段实现，包括（1）UH 2可行性阶段， 制定和实施方案和质量保证;招募受试者和临床疾病 分类;样本收集到中试样本处理和组学分析;数据标准化，管理 （2）UH 3实施和发现阶段， 识别不同的细胞网络和分子特征，以实现TMJD的新的合理分类， 合并症;并验证这些内型的唾液组学生物标志物。考虑到专家们聚集在一起 和计划，我们希望这些研究将提供所需的坚实基础和知识深度， 更合理地将患者分为TMJD和合并症亚型和严重程度类别;提供依据 为转化科学在诊断学，药理学和治疗学的新方向，基于多组学的 个别疾病亚型和为这些患者实施精准医疗;并定义 稳态和疾病的签名是特定的颞下颌关节，而不是approximular关节。

Project Summary/Abstract Temporomandibular Disorders (TMD) represent a spectrum of painful disorders that afflicts approximately 5 to 10% of the US population with approximate annual healthcare costs of $4 billion. Degenerative disorders, internal derangements including disc displacement and hypo/hyper-mobility, and arthralgia of the temporomandibular joint (TMJ), which together are referred to as TMJ disorders (TMJDs), are common in many subjects with TMD. No definitive etio-pathologic diagnostics are currently available, and treatments are non-specific and largely palliative. While a subset of TMJDs occur in isolation, a substantial proportion are associated with comorbidities such as headaches and/or fibromyalgia. These two distinct patient cohorts together with the peculiar predilection of TMJDs for women of reproductive age as opposed to the late onset of similar disorders in other joints, point to unique and complex interactions of systemic and local factors. As such, multi-omic signatures and cell networks at the local and systemic levels will facilitate specific diagnostics and clinically meaningful stratification of patients between and within each of these cohorts. Currently there is a substantial void in connecting the molecular multi-omic signatures and cellular networks / interactions with clinical disease subtypes, etiopathogenesis, progression and severity. Our long-term goal is to identify local and systemic single cell and biofluid multi-omic molecular profiles from a spectrum of TMJD subtypes and severities to delineate relationships between clinical phenotypes with deep omic signatures and cell networks that will nucleate new directions for rational and precision therapies, prognostics and prevention. We expect that such multi-omic analyses combined with case control and longitudinal clinical and imaging data will provide critical insights on novel molecular signatures and networks associated with specific disease subtypes / severity and the interactions between cell subpopulations in perpetuating or mitigating disease progression. These goals will be achieved through two milestones-based phases involving (1) a UH2 feasibility phase to develop and implement protocols and quality assurance; recruitment of subjects and clinical disease categorization; sample collection to pilot sample handling and omic assays; data standardization, management and access; and developing a robust statistical plan; and (2) a UH3 implementation and discovery phase to identify distinct cell networks and molecular signatures towards a new rational classification of TMJDs and comorbidities; and to validate salivary omics biomarkers of these endotypes. Given the assembled expertise and plans, we expect that these studies will provide strong foundations and depth of knowledge needed to more rationally stratify patients into TMJD and comorbidity subtypes and severity categories; provide the basis for new directions of translational science in diagnostics, prognostics and therapeutics based on multi-omics of individual disease subtypes and the implementation of precision medicine for these patients; and define homeostatic and disease signatures that are specific to the TMJ as opposed to appendicular joints.