Identification of the molecular interaction between joint tissues as a pathophysiological mechanism of osteoarthritis

鉴定关节组织之间的分子相互作用作为骨关节炎的病理生理机制

• 批准号: 9240581
• 负责人: Kyu Sang Joeng
• 金额: $ 12.67万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9240581
• 关键词: Affect; American; Binding; Bone Spur; Bone plates; Calcified; Cartilage; Cartilage Diseases; Cell Culture Techniques; Cells; Chondrocytes; Complex; Data; Degenerative polyarthritis; Disease; Disease Progression; FRAP1 gene; Functional disorder; Genetic; Genetic study; Goals; Human; Human Genetics; In Vitro; Inflammation; Joints; Knowledge; Ligaments; Ligands; Mediating; Mediator of activation protein; Medical; Medicine; Meniscus structure of joint; Molecular; Molecular Genetics; Mus; Organ; Osteoblasts; Osteocytes; Outcome Study; Pain; Pharmacology; Phenotype; Physical therapy; Regulation; Replacement Arthroplasty; Reporting; Research; Research Personnel; Role; Sclerosis; Signal Pathway; Signal Transduction; Signaling Molecule; TSC1 gene; Tendon structure; Testing; Therapeutic; Thick; Tissues; Training; WNT Signaling Pathway; WNT1 gene; Work; arthropathies; articular cartilage; base; beta catenin; bone; calcification; capsule; career; college; disability; end stage disease; gain of function; in vivo; insight; loss of function; mouse model; novel; prevent; public health relevance; skeletal; subchondral bone; therapeutic development

 DESCRIPTION (provided by applicant): Osteoarthritis (OA) is the most common degenerative disease of the joint and is the major cause of disability among people over 65 in the US. OA affects approximately 27 million Americans, and the annual financial burden of OA is more than $80 billion in the US. Medical therapies have been limited to pain relief, physical therapy, and joint replacement for end stage disease. There is a significant need for therapies to prevent OA progression and/or to reverse established disease. The progression of OA involves complex pathophysiological changes in the joint such as loss of articular cartilage, intra-articula inflammation, and subchondral bone sclerosis, suggesting that OA is not a simple cartilage disease but rather a disease of the whole joint as an organ. This conceptual shift of OA pathophysiology suggests that OA progression can be mediated by the crosstalk between joint tissues, but the molecular and cellular identity of the crosstalk remains to be elucidated. The overarching goal of this research is to define WNT1 as a novel signaling molecule mediating the crosstalk between articular cartilage and subchondral bone during OA progression and to evaluate mTORC1 signaling as a downstream mediator of WNT1 function in OA progression. The central hypothesis of this project is that induced WNT1 expression in subchondral osteocytes is involved in the pathophysiology of OA through the regulation of articular chondrocytes and subchondral osteoblasts and that mTORC1 signaling mediates the function of WNT1 in OA pathophysiology. To test this hypothesis, this project will utilize multiple genetic mouse models. The goal of Specific Aim 1 is to determine the function of WNT1 in the pathophysiology of OA. The goal of Specific Aim 2 will identify mTORC1 as a significant mediator of WNT1 function in the pathophysiology of OA. The significance of this study will be not only to determine novel molecular and cellular crosstalk as a pathophysiological mechanism of OA, but also to identify a specific signaling cascade contributing to OA progression. Therefore, the outcome of the study will provide new insight for the development of therapeutic strategies for OA treatment, especially for therapeutics that significantly inhibit OA progression. The Baylor College of Medicine possesses exceptional facilities for proposed work and the Department of Molecular and Human Genetics is committed to providing the best training for the applicant. Accomplishing this research will also provide sufficient training for critical skillsetsand in-depth knowledge for OA research, and will allow applicant to become a successful independent investigator focusing on the pathophysiological mechanism underlying OA.

 描述（由申请人提供）：骨关节炎（OA）是最常见的关节退行性疾病，是美国65岁以上人群残疾的主要原因。OA影响了大约2700万美国人，在美国，OA的年度经济负担超过800亿美元。医学治疗仅限于缓解疼痛，物理治疗和终末期疾病的关节置换。对于预防OA进展和/或逆转已确立疾病的疗法存在显著需求。OA的进展涉及关节中复杂的病理生理变化，例如关节软骨损失、关节内炎症和软骨下骨硬化，表明OA不是简单的软骨疾病，而是整个关节作为一个器官的疾病。OA病理生理学的这种概念转变表明，OA进展可以通过关节组织之间的串扰介导，但串扰的分子和细胞特性仍有待阐明。本研究的总体目标是将WNT 1定义为一种新型信号分子，在OA进展过程中介导关节软骨和软骨下骨之间的串扰，并评估mTORC 1信号作为OA进展中WNT 1功能的下游介导物。该项目的中心假设是，诱导的WNT 1在软骨下骨细胞中的表达通过调节关节软骨细胞和软骨下成骨细胞参与OA的病理生理学，并且mTORC 1信号传导介导WNT 1在OA病理生理学中的功能。为了验证这一假设，该项目将利用多种遗传小鼠模型。具体目标1的目标是确定WNT 1在OA病理生理学中的功能。具体目标2的目标是将mTORC 1确定为OA病理生理学中WNT 1功能的重要介质。本研究的意义不仅在于确定新的分子和细胞串扰作为OA的病理生理机制，而且还在于确定有助于OA进展的特定信号级联。因此，该研究的结果将为OA治疗的治疗策略的开发提供新的见解，特别是对于显著抑制OA进展的治疗方法。 贝勒医学院拥有用于拟议工作的卓越设施，分子和人类遗传学系致力于为申请人提供最好的培训。完成这项研究还将为OA研究的关键技能和深入知识提供足够的培训，并将使申请人成为一名成功的独立研究者，专注于OA的病理生理机制。