Targeting P21 positive senescent cells for alleviating TMJ degeneration

摘要 颞下颌关节退行性变是一种疼痛和衰弱的滑膜关节疾病， 影响到美国超过2000万人。肥胖、高龄和机械负荷是 是包括TMJ变性在内的许多疾病的最大风险因素。TMJ退变显著损害 通过造成急性和慢性疼痛来提高生活质量，从而使这一疾病成为全球健康问题和经济问题 疫情负担比例。TMJ退变的发生率预计将随着 在过去的二十年里，肥胖症的流行率急剧上升。因为目前还没有有效的治疗方法 在TMJ退行性变的肥胖者和老年人中，有一种临床上无法满足的有效需求 治疗TMJ退行性变的途径。 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 靶向p21高表达细胞用于治疗TMJ变性。我们的 最重要的假设是p21高细胞在肥胖、年龄相关和机械负荷中起中心作用。 诱导TMJ退变和靶向清除p21高表达细胞可减轻TMJ退变。至 验证这一假设，我们将确定：(1)骨软骨组织中p21高表达细胞在肥胖和衰老中的作用 诱导TMJ退变。使用一种新的可诱导的p21-cre ERT2 X TD-番茄小鼠，我们将研究 肥胖和衰老时p21高表达细胞对TMJ骨软骨组织动态平衡的影响(2) P21High细胞导致TMJ退变的病理生理机制。使用新的小鼠 模型(p21-cre ERT2 X TD-番茄X Rela Flox/Flox)，我们将检测NF-κB通路对衰老的影响。 TMJ内细胞变性。3)明确p21High细胞在创伤性TMJ损伤修复中的作用。P21-cre ERT2 X TD-Tomato小鼠将遭受TMJ创伤，我们将从基因上清除p21高 细胞创伤后，看看是否可以缓解TMJ-OA或修复受损的软骨。一个 结合了机械、免疫组织化学、分子生物学和成像技术 新的遗传小鼠模型将被用来研究拟议的特定目标。 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。 对肥胖和老年人TMJ的骨软骨组织进行了研究，并对 了解疾病机制并开发治疗干预措施。

Abstract Temporomandibular Joint (TMJ) degeneration is a painful and debilitating disease of the synovial joint, affecting over 20 million people in the United States. Obesity, advancing age and mechanical loading are greatest risk factor for 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 incidence of the TMJ degeneration is expected to rise substantially as the prevalence of obesity has risen dramatically over the last two-decades. As there is no effective treatment for the TMJ degeneration in an obese and aged individual, there is an unmet clinical need for an effective approach to treat TMJ degeneration. The current proposal seeks to address this unmet clinical challenge using a highly innovative approach of targeting p21 high cells both genetically and therapeutically for the treatment of TMJ degeneration. Our overarching hypothesis is that p21 high cells plays a central role in obesity, age-related and mechanical loading induced TMJ degeneration and targeted elimination of the p21 high cells may alleviate TMJ degeneration. To test this hypothesis, we will define: (1) the role of p21 high cells in osteochondral tissue in obesity and aging induced TMJ degeneration. Using a novel inducible p21-cre ERT2 X td-Tomato mice we will examine the effects of p21 high cells on the homeostasis of the osteochondral tissues of the TMJ in obesity and aging. (2) the pathophysiological mechanism by which p21high cells causes TMJ degeneration. Using the novel mice model (p21-cre ERT2 X td-Tomato X Rela flox/flox), we will examine the effect NF-κB pathway on the senescent cells in TMJ degeneration. 3) To define the role of p21high cells in traumatic TMJ injury and repair. p21-cre ERT2 X td-Tomato mice will be subjected to traumatic injury to TMJ and we will genetically clear the p21 high cells after traumatic injury to see whether we can alleviate TMJ-OA or repair the damaged cartilage. 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 obese and aged individual and to open new insight on understanding the disease mechanism and developing therapeutic interventions.