Role of Geroscience-Guided Therapeutics in Oral Health Problems of Aging

老年科学引导治疗在老龄化口腔健康问题中的作用

• 批准号: 10689203
• 负责人: Po-Jung Chen
• 金额: $ 15.35万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10689203
• 关键词: Acute Pain; Advisory Committees; Affect; Aging; Animals; Area; Atherosclerosis; Award; Biological; Botox; Career Choice; Cartilage; Cell Aging; Cell Cycle Arrest; Cells; Chondrocytes; Clinic; Clinical; Clinical Trials; Collaborations; Connective Tissue; Data; Degenerative Disorder; Degenerative polyarthritis; Dementia; Dentists; Development; Diabetes Mellitus; Disease; Elderly; Ensure; Epidemic; Female; Financial Hardship; Fracture; Functional disorder; Future; Geroscience; Goals; Heterogeneity; Homeostasis; Human; Impairment; In Vitro; Incidence; Individual; Infection; Intervention; Knee joint; Mandible; Medical; Mentors; Mus; Musculoskeletal; Nutritional status; Obesity; Operative Surgical Procedures; Oral health; Organ; Outcome; Pain Measurement; Pathology; Pathway interactions; Pattern; Persons; Pharmaceutical Preparations; Phenotype; Physiological; Play; Population; Predisposition; Process; Publishing; Quality of life; Reporter; Reporter Genes; Research; Risk Factors; Role; Science; Scientist; Structure; Temporomandibular Joint; Temporomandibular Joint Disorders; Testing; Therapeutic; Thick; Time; Tissues; Training; Training Programs; Transgenic Organisms; Translating; United States; Workload; X-Ray Computed Tomography; age related; aged; aging demographic; aging demography; aging population; biomechanical test; career; cell type; chronic pain; condylar cartilage; disability; drug development; effective therapy; experimental group; global health; human old age (65+); implantation; improved; in vivo; insight; joint destruction; joint loading; male; mechanical load; microCT; mouse model; multidisciplinary; novel; novel strategies; novel therapeutic intervention; novel therapeutics; osteochondral tissue; prevent; response; sarcopenia; senescence; small molecule; subchondral bone; success; transcriptome sequencing; transcriptomics

Professional Development: This GEMSSTAR application describes 2 years training program to further my career aspirations to become an independent dentist-scientist in geriatric oral health field. My goal is to gain additional training under the leading scientists to achieve my ultimate goal of developing novel approaches to treat/alleviate age-related TMJ degeneration. This award will support, guide and importantly facilitate my following goals: (1) To acquire additional training in geroscience. (2) To complete the studies outlined in Specific Aims and translate from bench research to clinic. (3) To develop a deeper collaboration with multidisciplinary team. To achieve the listed goal, I have assembled a career advisory committee to help develop my academic career in the most effective way. Also, my mentors in areas that are beyond my current field of expertise will ensure the success of my projected aims. Science: Aging affects all organs and tissues of the body and leads to 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 United States and the global ageing populations are projected to grow exponentially over the next several decades, the incidence of the TMJ degenerative disorders is also 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 degeneration associated with old age. Our central hypothesis is that concurrent administration of senolytics and mechanical loading will have a synergistic anabolic effect on the cartilage of TMJ. The hypothesis will be tested by following specific aims: Aim 1: To determine if intermittent mechanical loading augments the beneficial effects of intermittent senolytics on TMJ cartilage. We will utilize both male and female triple transgenic reporter mice (Col1a1X Col2a1XCol10a1 triple transgenic reporter mice) following D+Q/vehicle treatment and mechanical loading/unloading with botox. The micro-CT image, biomechanical testing, histomorphometry, RNA sequencing, and pain measurement will be done to determine outcome. Aim 2: To define the biological mechanism by which senolytics and intermittent mechanical loading alleviates TMJ degeneration in older adults. We will leverage single cell transcriptomics (SCT) to reveal the heterogeneity and conserved transcriptomic signatures of Col1a1 and Col10a1 cells in vivo in different experimental groups. We will assess the percentage of Col1a1, Col2a1 and Col10a1 cells across different cell types (clusters) in different experimental groups to gain insights on the conserved transcriptomic signature of Col1a1 and Col10a1 cells regardless of cell type, which could be invaluable for future drug development.

专业发展：此 GEMSSTAR 应用程序描述了 2 年培训计划，以进一步提升我的能力 职业愿望是成为老年口腔健康领域的独立牙医科学家。我的目标是获得 在顶尖科学家的指导下进行额外培训，以实现我开发新方法的最终目标 治疗/缓解与年龄相关的颞下颌关节退化。该奖项将支持、指导并重要地促进我 以下目标： (1) 获得老年科学方面的额外培训。 (2) 完成上文中概述的研究 具体目标并将实验室研究转化为临床。 （三）深化与中外合作 多学科团队。为了实现列出的目标，我组建了一个职业咨询委员会来帮助 以最有效的方式发展我的学术生涯。此外，我的导师在超出我的领域 当前的专业领域将确保我预期目标的成功。 科学：衰老会影响身体的所有器官和组织，并导致许多疾病，包括颞下颌关节紊乱病 退化。颞下颌关节退化会引起急性和慢性疼痛，严重损害生活质量， 从而使这种疾病成为全球健康问题和流行病程度的经济负担。联合 预计各州和全球老龄化人口将在未来几年内呈指数级增长 几十年来，颞下颌关节退行性疾病的发病率预计也会大幅上升。因为有 对于老年人的颞下颌变性，目前尚无有效的治疗方法，因此临床需求尚未得到满足 治疗与老年相关的颞下颌关节退化的有效方法。 我们的中心假设是，同时施用 senolytics 和机械负荷将会产生 对 TMJ 软骨的协同合成代谢作用。该假设将通过以下具体目标进行检验： 目标 1：确定间歇性机械负载是否会增强间歇性机械负载的有益效果 对 TMJ 软骨的 senolytics。我们将利用雄性和雌性三重转基因报告小鼠 (Col1a1X Col2a1XCol10a1 三重转基因报告小鼠）在 D+Q/载体处理和机械治疗后 使用肉毒杆菌装载/卸载。显微CT图像、生物力学测试、组织形态计量学、RNA 将进行测序和疼痛测量以确定结果。目标 2：定义生物学 senolytics 和间歇性机械负荷减轻老年人 TMJ 退化的机制 成年人。我们将利用单细胞转录组学（SCT）来揭示异质性和保守性 不同实验组中 Col1a1 和 Col10a1 细胞体内的转录组特征。我们将 评估不同细胞类型（簇）中 Col1a1、Col2a1 和 Col10a1 细胞的百分比 实验组深入了解 Col1a1 和 Col10a1 的保守转录组特征 无论细胞类型如何，这对于未来的药物开发都是无价的。