Targeting P21 positive senescent cells for alleviating TMJ degeneration

摘要 颞下颌关节（TMJ）变性是一种疼痛和使人衰弱的滑膜关节疾病， 影响了美国两千万人肥胖、年龄增长和机械负荷是 这是许多疾病的最大风险因素，包括TMJ变性。颞下颌关节退行性变显著损害了 通过引起急性和慢性疼痛，从而使这种疾病成为全球健康问题和金融危机， 疫情负担比例。颞下颌关节退化的发病率预计将大幅上升， 在过去的二十年中，肥胖症的流行率急剧上升。由于没有有效的治疗方法， 在肥胖和老年个体中的TMJ变性中，存在对有效治疗TMJ变性的未满足的临床需求。 治疗颞下颌关节退行性变的方法。 目前的提案旨在通过一种高度创新的方法来解决这一尚未解决的临床挑战， 在基因上和治疗上靶向p21高细胞用于治疗TMJ变性。我们 总体假设是，p21高细胞在肥胖、年龄相关和机械负荷中起核心作用 诱导TMJ变性和靶向清除p21高表达细胞可减轻TMJ变性。到 为了验证这一假设，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 导致TMJ变性。使用一种新的可诱导的p21-cre ERT 2 X td-番茄小鼠，我们将检查 p21高表达细胞对肥胖和衰老颞下颌关节骨软骨组织稳态的影响。（二） p21 high细胞导致TMJ变性的病理生理机制。使用新的老鼠 模型（p21-cre ERT 2 X td-Tomato X Rela flox/flox）中，我们将检测NF-κB通路在衰老中的作用。 颞下颌关节退行性变的细胞。3)目的探讨p21 high细胞在创伤性颞下颌关节损伤修复中的作用。p21-cre ERT 2 X td-Tomato小鼠将遭受TMJ创伤性损伤，我们将从基因上清除p21高表达 细胞创伤损伤后，看看我们是否可以减轻TMJ-OA或修复受损的软骨。一 结合机械、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用于研究所提出的具体目标。 拟议的项目具有揭示控制体内平衡的新调节途径的巨大潜力 的骨软骨组织的颞下颌关节在肥胖和老年人，并打开新的见解， 了解疾病机制并制定治疗干预措施。

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.