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

职业发展：这个GEMSSTAR应用程序描述了两年的培训计划，以进一步提高我的 有志成为老年口腔健康领域的一名独立牙医兼科学家。我的目标是获得 在顶尖科学家的指导下进行额外的培训，以实现我开发新方法的最终目标 治疗/减轻年龄相关性TMJ退行性变。该奖项将支持、指导并重要地促进我的 以下目标：(1)获得老年科学方面的额外培训。(2)完成下列各项研究 明确目标，并将实验研究转化为临床研究。(3)与中国深化合作 多学科团队。为了实现列出的目标，我已经成立了一个职业咨询委员会来帮助 以最有效的方式发展我的学术事业。此外，我的导师在我无法涉足的领域 目前的专业领域将确保我计划的目标的成功。 科学：衰老影响身体所有器官和组织并导致包括TMJ在内的许多疾病 退化。TMJ变性会引起急性和慢性疼痛，从而显著损害生活质量， 从而使这一疾病成为一个全球性的卫生问题和流行比例的经济负担。美联队 预计未来几年，各州和全球老龄化人口将呈指数级增长 几十年来，TMJ退行性疾病的发病率预计也将大幅上升。就像现在一样 对于老年人的TMJ退行性变没有有效的治疗方法，临床上对 治疗老年性TMJ退行性变的有效方法。 我们的中心假设是，同时给予感觉剂和机械负荷将有一个 对TMJ软骨的协同合成代谢作用。这一假设将通过以下具体目标进行检验： 目的1：确定间歇性机械负荷是否增加了间歇性机械负荷的益处 TMJ软骨上的感光剂。我们将利用雄性和雌性三重转基因报告小鼠(Col1a1X Col2a1XCol10a1三重转基因报告鼠)经D+Q/Vehicle治疗后 用肉毒杆菌装卸。显微CT图像、生物力学测试、组织形态计量学、RNA 将进行排序和疼痛测量以确定结果。目标2：定义生物学 感觉剂和间歇性机械负荷减轻老年人TMJ退变的机制 成年人。我们将利用单细胞转录学(SCT)来揭示异质性和保守性 不同实验组体内Col1a1和Col10a1细胞的转录特征。我们会 评估COL1a1、COL2a1和COL10a1细胞在不同细胞类型(集群)中的百分比 实验小组深入了解Col1a1和Col10a1的保守转录签名 无论细胞类型如何，这对未来的药物开发都可能是无价的。

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.