Targeting P21 positive senescent cells for alleviating TMJ degeneration

靶向 P21 阳性衰老细胞减轻 TMJ 变性

基本信息

批准号：
10892710
负责人：
Sumit Yadav
金额：
$ 30.7万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-11 至 2024-08-10
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10892710
关键词：
Acceleration Acute Pain Address Affect Aging Automobile Driving Cartilage Cartilage injury Cell Aging Cells Clinical Coupled Data Degenerative Disorder Deterioration Disease Disease Progression Elderly Enterobacteria phage P1 Cre recombinase Epidemic FDA approved Financial Hardship Future Genes Genetic Goals Growth Heterogeneity Homeostasis Imaging Techniques Impairment Incidence Incisor Individual Inflammatory Response Intervention Joint repair Knowledge LoxP-flanked allele Mechanics Metals Methodology Modeling Molecular Molecular Biology Monitor Mus Obese Mice Obesity Older Population Outcome Pain Pathway interactions Patients Persons Play Population Prevalence Public Health Publishing Quality of life Regulatory Pathway Replacement Arthroplasty Risk Factors Role Societies Synovial joint Temporomandibular Joint Temporomandibular Joint Disorders Testing Therapeutic Therapeutic Intervention Transgenic Mice Trauma Traumatic injury United States Work age related aged cell type chronic pain cost effective therapy global health in vivo inducible Cre innovation insight joint destruction joint injury mechanical load molecular imaging mouse model novel osteochondral tissue pharmacologic prevent promoter repaired research clinical testing senescence transcriptomics

项目摘要

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.

抽象的颞下颌关节（TMJ）变性是滑膜关节的痛苦而令人衰弱的疾病，在美国影响超过2000万人。肥胖，年龄和机械负荷是许多疾病包括TMJ变性的最大风险因素。 TMJ变性大大损害了通过引起急性和慢性疼痛来生活质量，从而使该疾病成为全球健康问题和财务流行比例的负担。预计TMJ变性的事件将大幅上升在过去的两个十年中，肥胖症的患病率急剧上升。因为没有有效的治疗方法肥胖和老年人的TMJ变性，对有效的临床需求未满足治疗TMJ变性的方法。当前的建议旨在通过高度创新的方法来应对这一未满足的临床挑战靶向P21高细胞均普遍和治疗，用于治疗TMJ变性。我们的总体假设是p21高细胞在肥胖症，与年龄相关和机械载荷中起着核心作用诱导的TMJ变性并靶向消除P21高细胞可能会减轻TMJ变性。到检验该假设，我们将定义：（1）P21高细胞在骨软骨组织中的作用在肥胖症和衰老中诱导TMJ变性。使用新型诱导的P21-CRE ERT2 X TD-TOMATO小鼠，我们将检查 p21高细胞对肥胖和衰老中TMJ骨软骨组织稳态的影响。（2） P21高细胞引起TMJ变性的病理生理机制。使用新颖的小鼠模型（p21-cre ert2 x td-tomato x rela flox/flox），我们将检查效果NF-κB途径对感觉的影响 TMJ变性的细胞。 3）定义p21高细胞在创伤性TMJ损伤和修复中的作用。 p21-cre ERT2 X TD-TOMATO小鼠将对TMJ造成创伤性损伤，我们通常会清除P21高创伤后的细胞，以查看我们是否可以减轻TMJ-OA或修复受损的软骨。一个机械，免疫组织化学，分子生物学和成像技术与结合结合新型遗传小鼠模型将用于研究提出的特定目的。拟议的项目具有揭示控制体内平衡的新监管途径的巨大潜力肥胖和老年人中TMJ的骨软骨组织的了解疾病机制并发展治疗干预措施。