Local and Systemic Multi-Omics of TMJ Disorders

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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.