Saturday, September 7, 2024
9/7/2024
PROJECT SUMMARY/ABSTRACT Temporomandibular joint (TMJ) osteoarthritis (TMJOA) is a degenerative disease of the joint. It has been challenging to manage and treat TMJOA due to our limited understanding of the molecular, cellular, and neuronal mechanisms underlying TMJOA. The goal of this proposal is to use multi-modal single-cell and imaging technologies to establish a high-dimensional, comprehensive molecular, cellular, and innervation map of TMJ under healthy and OA conditions in mouse models that mimic human TMJOA. We will further validate Netrin- 1/Dcc as the potential therapeutic target of TMJOA. A major strength of this collaborative project is to integrate the findings, skills, and distinct expertise of investigators including PI Jianfu Chen (Neuroscience), co-Is Mildred Embree and Yang Chai (Craniofacial biology and TMJOA), collaborator Xu Cao (Neuroskeletal pain) and Hu Zhao (TESOS volume imaging), which cannot otherwise be accomplished by the individual investigators separately. Strong published and preliminary studies support comprehensive team of scientific approaches in unveiling the mechanisms of TMJOA, including different TMJOA mouse models, methodology for joint pain behavior, dynamic changes in joint pathologies and innervation during OA, 3-D imaging methods to map sensory nerve connectome in the TMJ at micron resolution, antegrade and retrograde tracing of joint innervation, chemogenetic functional assays of neural circuits, and single cell RNA-sequencing approaches. Importantly, our preliminary studies have identified Netrin-1/Dcc as key mediators of TMJ cell-cell interaction and potential therapeutic targets for mitigating TMJOA pain. These exciting preliminary data put us in a unique position to generate the first comprehensive molecular, cellular, and innervation map of TMJ with or without OA and to identify new therapeutic targets. Our guiding hypothesis is that TMJOA causes significant alterations in chromatin accessibility and gene expression of disease relevant cell types including osteoclasts and synovial fibroblasts in TMJ, which in turn cause maladaptive nociceptive innervation leading to joint pain and degeneration. To test our hypothesis, we will: (1) create a comprehensive single-cell transcriptomic and epigenomic cell atlas for the TMJ in TMJOA model mice and identify molecular changes that accompany TMJOA in each cell type. (2) functionally map TMJ nociceptive innervation during OA progression. (3) validate Netrin-1/Dcc as mediators and therapeutic targets of TMJOA pain.
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