Role of Geroscience-Guided Therapeutics in Oral Health Problems of Aging

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Professional Development: This GEMSSTAR application describes 2 years training program to further my career aspirations to become an independent dentist-scientist in geriatric oral health field. My goal is to gain additional training under the leading scientists to achieve my ultimate goal of developing novel approaches to treat/alleviate age-related TMJ degeneration. This award will support, guide and importantly facilitate my following goals: (1) To acquire additional training in geroscience. (2) To complete the studies outlined in Specific Aims and translate from bench research to clinic. (3) To develop a deeper collaboration with multidisciplinary team. To achieve the listed goal, I have assembled a career advisory committee to help develop my academic career in the most effective way. Also, my mentors in areas that are beyond my current field of expertise will ensure the success of my projected aims. Science: Aging affects all organs and tissues of the body and leads to many diseases, including TMJ degeneration. TMJ degeneration significantly impair the quality of life by causing acute and chronic pain, thus making this disease a global health issue and a financial burden of epidemic proportion. The United States and the global ageing populations are projected to grow exponentially over the next several decades, the incidence of the TMJ degenerative disorders is also expected to rise substantially. As there is no effective treatment for the TMJ degeneration in an aged individual, there is an unmet clinical need for an effective approach to treat TMJ degeneration associated with old age. Our central hypothesis is that concurrent administration of senolytics and mechanical loading will have a synergistic anabolic effect on the cartilage of TMJ. The hypothesis will be tested by following specific aims: Aim 1: To determine if intermittent mechanical loading augments the beneficial effects of intermittent senolytics on TMJ cartilage. We will utilize both male and female triple transgenic reporter mice (Col1a1X Col2a1XCol10a1 triple transgenic reporter mice) following D+Q/vehicle treatment and mechanical loading/unloading with botox. The micro-CT image, biomechanical testing, histomorphometry, RNA sequencing, and pain measurement will be done to determine outcome. Aim 2: To define the biological mechanism by which senolytics and intermittent mechanical loading alleviates TMJ degeneration in older adults. We will leverage single cell transcriptomics (SCT) to reveal the heterogeneity and conserved transcriptomic signatures of Col1a1 and Col10a1 cells in vivo in different experimental groups. We will assess the percentage of Col1a1, Col2a1 and Col10a1 cells across different cell types (clusters) in different experimental groups to gain insights on the conserved transcriptomic signature of Col1a1 and Col10a1 cells regardless of cell type, which could be invaluable for future drug development.