Cellular Senescence in mediating age related TMJ Degeneration

摘要 年龄增长是许多疾病的最大风险因素，包括颞下颌关节退行性疾病。TMJ 变性通过引起急性和慢性疼痛显著损害生活质量，从而使这种疾病 一个全球性的健康问题和流行病比例的财政负担。随着美国和世界 随着未来几十年人口老龄化，预计颞下颌关节退行性疾病的发病率 大幅上涨。由于对老年人的TMJ退化没有有效的治疗方法， 对治疗与老年相关的TMJ退化的有效方法的未满足的临床需求。 目前的提案旨在使用高度创新的方法来解决这一尚未满足的临床挑战 （senolytics），其之前从未被测试用于治疗TMJ退化。我们的总体 假设是细胞衰老在与年龄相关的TMJ退化中起核心作用， 清除衰老细胞可防止或逆转TMJ变性。为了验证这些假设，我们 本研究将探讨：（1）用抗衰老药物清除衰老细胞是否能抑制或延缓衰老的发生 TMJ骨软骨组织的相关变性？使用三重转基因报告小鼠（Col1a1 X Col2a1 X Col10a1），我们将研究衰老药物对细胞内稳态的影响和机制。 TMJ的骨软骨组织。(2)将衰老细胞转移到年轻小鼠体内是否会使 颞下颌关节骨软骨组织更容易退化？我们将移植衰老或非衰老的 对照细胞植入12周龄的雄性和雌性三重转基因报告小鼠，然后评估 动物被安乐死后的退化。结合机械免疫组织化学分子生物学 生物学和成像技术与新的遗传小鼠模型相结合，将用于研究拟议的 具体目标。 该项目具有揭示控制体内平衡的新调控途径的巨大潜力 的骨软骨组织的TMJ在一个老年人，并打开新的见解，了解 疾病机制和开发治疗干预措施。

Abstract Advancing age is the single greatest risk factor for many diseases including TMJ degenerative disorders. 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. As the United States and the world population ages over the next several decades, the incidence of the TMJ degenerative disorders are 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 degenration associated with old age. The current proposal seeks to address this unmet clinical challenge using a highly innovative approach (senolytics) that has never been tested before for the treatment of TMJ degenration. Our overarching hypothesis is that cellular senescence plays a central role in age-related TMJ degeneration and targeted elimination of the senescent cells may prevent or reverse the TMJ degeneration. To test this hypotheses, we will examine: (1) Does eliminating the senescent cells by senolytics can inhibit or delay the development of age related degeneration of the osteochondral tissues of TMJ? Using a triple transgenic reporter mouse (Col1a1 X Col2a1 X Col10a1), we will examine the effects and mechanism of senolytics on the homeostasis of the osteochondral tissues of the TMJ. (2) Does transfer of senescent cells into the young mice make the osteochondral tissue of TMJ more prone to degeneration? We will transplant the senescent or non-senescent control cells into 12-week-old male and female triple transgenic reporter mice and then assess the the degeneration after the animals are euthanized. A combination of mechanical, immunohistochemical, molecular biology and imaging techniques coupled with novel genetic mice models will be used to study the proposed specific aims. The proposed project has the immense potential to reveal new regulatory pathways that controls homeostasis of the osteochondral tissues of the TMJ in an aged individual and to open new insight on understanding the disease mechanism and developing therapeutic interventions.