Cellular Senescence in mediating age related TMJ Degeneration

摘要 年龄增长是包括TMJ退行性疾病在内的许多疾病的最大危险因素。TMJ 变性会引起急性和慢性疼痛，从而严重损害生活质量，从而使这种疾病 这是一个全球性的卫生问题，也是一个流行病比例的财政负担。就像美国和世界 人口老龄化在未来几十年内，TMJ退行性疾病的发病率有望上升 大幅上涨。由于老年人的TMJ退行性变没有有效的治疗方法，因此有 一个尚未得到满足的临床需求，需要一种有效的方法来治疗与老年相关的TMJ退行性变。 目前的提案寻求使用高度创新的方法来解决这一未得到满足的临床挑战。 (感觉剂)以前从未被测试过用于治疗TMJ退行性变。我们最重要的是 假设细胞衰老在年龄相关的TMJ退变中起中心作用，并有针对性 消除衰老细胞可防止或逆转TMJ退变。为了检验这一假设，我们 将研究：(1)用促衰老药物消除衰老细胞是否能抑制或延缓衰老的发展 TMJ骨软骨组织的相关性退变？使用三重转基因报告鼠(Col1a1 X Col2a1 X Col10a1)，我们将研究感受剂对细胞内稳态的影响及其机制。 TMJ的骨软骨组织。(2)将衰老细胞转移到幼鼠体内是否使 TMJ的骨软骨组织更容易退变？我们将移植衰老或非衰老的 将对照细胞转化为12周龄雄性和雌性三重转基因报告小鼠，然后评估 在动物被安乐死后退化。机械的、免疫组织化学的、分子的 生物学和成像技术结合新的遗传小鼠模型将被用于研究拟议的 明确的目标。 拟议中的项目具有巨大的潜力，可以揭示控制动态平衡的新的调控途径。 对老年人TMJ的骨软骨组织进行研究，为理解 疾病机制和发展治疗干预措施。

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.