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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

基本信息

批准号：
10517869
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
项目类别：
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/10517869
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 Due Process 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 Publishing Quality of life Reporter 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 population biomechanical test career cell type chronic pain condylar cartilage disability drug development effective therapy experimental group global health human old age (65+)implantation 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

项目摘要

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年的培训计划，以进一步我的职业抱负是成为老年口腔健康领域的独立牙医科学家。我的目标是在顶尖科学家的指导下进行额外的培训，以实现我开发新方法的最终目标治疗/缓解与年龄相关的TMJ退化。这个奖项将支持，指导和重要的是促进我的目标如下：（1）获得老年科学方面的额外培训。(2)为了完成具体的目标，并从实验室研究转化为临床。(3)为了更深入地与多学科团队。为了实现上述目标，我组建了一个职业咨询委员会，以最有效的方式发展我的学术生涯。此外，我的导师在领域，超出了我的目前的专业知识将确保我的预期目标的成功。科学：衰老会影响身体的所有器官和组织，并导致许多疾病，包括颞下颌关节退化颞下颌关节变性通过引起急性和慢性疼痛而显著损害生活质量，从而使这种疾病成为全球性的健康问题和流行病比例的财政负担。联合预计在今后几年中，各国和全球老龄人口将呈指数级增长，在未来的几十年里，颞下颌关节退行性疾病的发病率预计也将大幅上升。由于对于老年人的TMJ变性没有有效的治疗，是治疗老年性颞下颌关节退行性变的有效方法。我们的中心假设是，同时给予senolytics和机械负荷，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：目的1：确定间歇性机械负荷是否会增加间歇性机械负荷的有益效果。颞下颌关节软骨上的衰老抑制剂我们将利用雄性和雌性三重转基因报告小鼠（Col 1a 1X Col 2a 1XCol 10a 1三重转基因报告基因小鼠）注射肉毒杆菌显微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：定义生物学老年痴呆症和间歇性机械负荷加重老年人TMJ退行性变的机制成年人了我们将利用单细胞转录组学（SCT）来揭示异质性和保守性。不同实验组中体内Col 1a 1和Col 10a 1细胞的转录组学特征。我们将评估不同细胞类型（簇）中Col 1a 1、Col 2a 1和Col 10a 1细胞的百分比，实验组，以深入了解Col 1a 1和Col 10a 1的保守转录组特征无论细胞类型如何，这对未来的药物开发都是非常宝贵的。