Studies of Joint Aging and Osteoarthritis

关节衰老和骨关节炎的研究

• 批准号: 7623639
• 负责人: Martin K Lotz
• 金额: $ 212.56万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-06-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7623639
• 关键词: Studies; Joint; Aging; Osteoarthritis

DESCRIPTION (provided by applicant): This competing renewal continues to utilize human knee joints from donors across the adult age spectrum to establish phenotypic changes in articular cartilage and chondrocytes that are characteristic of normal joint aging and may predispose to the development of osteoarthritis (OA). The overall goal of this program is to begin with phenotype identification, proceed to elucidation of mechanisms and key cellular and molecular abnormalities in order to provide new directions for correcting aging-associated risk factors for OA and therapeutic interventions for established OA. Access to human tissues provides a unique opportunity to test the human and clinical relevance of novel basic and molecular mechanisms not only through correlative studies but also through an array of comprehensive in vitro studies with cells isolated from human tissues. The overall hypothesis proposes that cartilage aging is associated with loss and dysfunction that differentially affects cartilage cell subpopulations. Chondrocytes are compromised in function by aging-associated changes in signaling mechanisms and the inflammatory milieu of OA. The proposed program will continue the existing cores (A: Administration; B and C now combined into Core B: Tissue Acquisition, Morphology, and Cell Culture). The following 3 projects are proposed: Project 1, "Chondrocyte subpopulations in aging and osteoarthritis" (PI: M. Lotz) will characterize chondrocyte subpopulations and the role of Sox9-dependent activation of chondrocytes in normal and aging cartilage. Project 2, "Dysfunctional chondrocyte differentiation in aging cartilage" (PI: R. Terkeltaub) addresses the regulation of articular chondrocyte hypertrophy by altered Pi and PPi metabolism with focus on specific enzymes (NPP1, TNAP) and transporters (Ank, Pit-1). Project 4, "Mechanobiology of human articular cartilage degeneration: aging and osteoarthritis" (PI: R. Sah) will analyze biomechanical mechanisms of early and advanced cartilage degeneration and determine consequences for chondrocyte function and survival. Collectively, the results from the proposed studies will add important new information on chondrocyte biology, cartilage aging, and osteoarthritis pathophysiology. RELEVANCE: Joint aging is the major risk factor for the osteoarthritis, the most prevalent joint disease. Therapies that modify the progressive cartilage destruction process are not available. This program represents a comprehensive analysis of cellular end extracellular matrix changes that are associated with aging and osteoarthritis. Defining mechanisms of healthy joint aging and pathogenetic mechanisms of osteoarthritis has the potential to lead to new osteoarthritis markers and therapies. PRINCIPAL INVESTIGATOR: Dr. Martin Lotz holds the appointments of Professor in the Department of Molecular and Experimental Medicine and Head of the Division of Arthritis Research at the Scripps Research Institute. He also has a faculty appointment at the University of California, San Diego, the other institution involved in the program. He has been a part of this program since its inception in 1988 and has served as Principal Investigator (PI) since 1996. Dr. Lotz is an established investigator in the fields of cartilage biology and osteoarthritis pathogenesis and is internationally recognized for his research. His participation and leadership constitute a major strength of this program project. REVIEW OF INDIVIDUAL COMPONENTS OF THE PROGRAM PROJECT CORE A - ADMINISTRATION; Dr. Martin K. Lotz, Core Leader DESCRIPTION (provided by applicant): The central theme of the Program is to study aging of human articular cartilage and chondrocytes and its relationship to osteoarthritis. The Administrative Core will focus efforts of the cores and projects on this topic, advance hypotheses and research directions, and ascertain scientific progress. The Specific Aims of the Administrative Core are: 1. Monitor scientific progress in the individual projects. The core is responsible for stimulating and focusing discussions among the participants of the Program on aging of human cartilage. Regular monthly seminars will be held where each project presents a progress report. At annual meetings with the Scientific Advisory Committee, progress is evaluated and efforts are redirected. 2. Promote interactions among the investigators in the Program. Wherever possible, potential interactions will be identified and brought to successful realization. Specific themes for interactions have been defined and productivity in terms of co-authored publications will be reviewed annually. 3. Support young scientists and development of new projects. Young scientists are included as coinvestigators in this program. They are supported through mentoring, access to human tissues and assistance in preliminary data generation and statistical analysis for grant applications. 4. Provide access to cartilage samples. 5. Establish and maintain central database. The Administrative Core has established and will maintain a database with information on all cartilage samples that are studied in the Program. Research data from the Projects will be entered into the central database for analysis. Statistical analysis. We will perform data analysis for Core B and the individual projects and establish correlations between measurements obtained in the 3 projects. 7. Coordinate all fiscal activities of the Program. 8. Ascertain responsible conduct of research. This Program is using human tissue and animals. The Administrative Core surveys that all activities involving human tissue and animals are performed in accordance with HIPPA, NIH, and IACUC guidelines. 9. Enforce safety measures for work with hazardous materials. RELEVANCE: The central theme of the Program is to study aging of human articular cartilage and chondrocytes and its relationship to osteoarthritis. The Administrative Core will focus efforts of the cores and projects on this topic, advance hypotheses and research directions, and ascertain scientific progress.

描述（由申请人提供）：这种竞争性的更新继续利用来自不同成人年龄范围的捐赠者的人类膝关节来建立关节软骨和软骨细胞的表型变化，这些变化是正常关节老化的特征，并且可能导致骨关节炎（OA）的发展。该项目的总体目标是从表型鉴定开始，继续阐明机制以及关键的细胞和分子异常，以便为纠正与衰老相关的 OA 危险因素和针对既定 OA 的治疗干预提供新方向。获取人体组织提供了一个独特的机会，不仅可以通过相关研究，还可以通过对从人体组织中分离出的细胞进行一系列全面的体外研究，来测试新型基础和分子机制的人类和临床相关性。总体假设认为，软骨衰老与软骨细胞亚群的损失和功能障碍相关，而软骨细胞亚群的损失和功能障碍对软骨细胞亚群有不同的影响。与衰老相关的信号机制和 OA 炎症环境的变化会损害软骨细胞的功能。拟议的计划将延续现有的核心（A：管理；B 和 C 现在合并为核心 B：组织采集、形态学和细胞培养）。提出了以下 3 个项目： 项目 1，“衰老和骨关节炎中的软骨细胞亚群”（PI：M. Lotz）将描述软骨细胞亚群的特征以及软骨细胞 Sox9 依赖性激活在正常和衰老软骨中的作用。项目 2，“老化软骨中功能失调的软骨细胞分化”（PI：R. Terkeltaub）通过改变 Pi 和 PPi 代谢来调节关节软骨细胞肥大，重点关注特定酶（NPP1、TNAP）和转运蛋白（Ank、Pit-1） 。项目 4“人类关节软骨退变的力学生物学：衰老和骨关节炎”（负责人：R. Sah）将分析早期和晚期软骨退变的生物力学机制，并确定对软骨细胞功能和存活的影响。总的来说，拟议研究的结果将为软骨细胞生物学、软骨老化和骨关节炎病理生理学添加重要的新信息。 相关性：关节老化是骨关节炎（最常见的关节疾病）的主要危险因素。目前还没有改变渐进性软骨破坏过程的疗法。该程序对与衰老和骨关节炎相关的细胞末端细胞外基质变化进行了全面分析。定义健康关节衰老的机制和骨关节炎的发病机制有可能带来新的骨关节炎标志物和治疗方法。 主要研究者：Martin Lotz 博士担任斯克里普斯研究所分子与实验医学系教授和关节炎研究部主任。他还在参与该计划的另一所机构——加州大学圣地亚哥分校担任教员。自 1988 年该项目启动以来，他一直是该项目的一部分，并自 1996 年起担任首席研究员 (PI)。Lotz 博士是软骨生物学和骨关节炎发病机制领域的知名研究者，其研究成果得到国际认可。他的参与和领导构成了该计划项目的主要优势。 计划项目各个组成部分的审查 核心A——管理； Martin K. Lotz 博士，核心领导者 描述（由申请人提供）：该计划的中心主题是研究人类关节软骨和软骨细胞的衰老及其与骨关节炎的关系。行政核心将集中核心和项目在该主题上的工作，提出假设和研究方向，并确定科学进展。行政核心的具体目标是： 1. 监测各个项目的科学进展。核心负责激发和集中该计划参与者之间关于人类软骨老化的讨论。每月定期举行研讨会，每个项目都会提交进度报告。在与科学咨询委员会的年度会议上，评估进展并调整努力方向。 2. 促进计划中研究者之间的互动。只要有可能，就会发现潜在的互动并成功实现。互动的具体主题已经确定，并且每年都会审查共同撰写出版物的生产力。 3. 支持青年科学家和新项目的开发。年轻科学家被列为该计划的共同研究者。他们通过指导、获取人体组织以及协助资助申请的初步数据生成和统计分析来获得支持。 4. 提供软骨样本的获取。 5.建立和维护中央数据库。管理核心已经建立并将维护一个数据库，其中包含该计划中研究的所有软​​骨样本的信息。项目的研究数据将输入中央数据库进行分析。统计分析。我们将对核心 B 和各个项目进行数据分析，并建立 3 个项目中获得的测量值之间的相关性。 7. 协调该计划的所有财务活动。 8. 确定负责任的研究行为。该计划使用人体组织和动物。行政核心调查显示，所有涉及人体组织和动物的活动均按照 HIPPA、NIH 和 IACUC 指南进行。 9. 执行危险材料作业的安全措施。 相关性：该计划的中心主题是研究人类关节软骨和软骨细胞的衰老及其与骨关节炎的关系。行政核心将集中核心和项目在该主题上的工作，提出假设和研究方向，并确定科学进展。