Identification of the Molecular Interaction Between Joint Tissues as a Pathophysiological Mechanism of Osteoarthritis

 描述(申请人提供)：骨关节炎(OA)是最常见的关节退行性疾病，也是美国65岁以上人群残疾的主要原因。美国约有2700万美国人受到办公自动化的影响，在美国，每年办公自动化造成的经济负担超过800亿美元。医学治疗一直局限于缓解疼痛、物理治疗和终末期疾病的关节置换。对于预防骨性关节炎进展和/或逆转既得性疾病的治疗方法有着重要的需求。骨关节炎的进展涉及关节的复杂病理生理变化，如关节软骨丢失、关节内炎症和软骨下骨硬化，提示骨关节炎不是一种简单的软骨疾病，而是一种整个关节作为一个器官的疾病。骨性关节炎病理生理学的这一概念转变表明，骨性关节炎的进展可以通过关节组织之间的串扰来调节，但串扰的分子和细胞身份仍有待阐明。本研究的主要目标是将WNT1定义为一种新的信号分子，介导关节软骨和软骨下骨之间的串扰，并评价mTORC1信号作为WNT1在OA进展中作用的下游介导物。该项目的中心假设是，WNT1在软骨下骨细胞中的诱导表达通过对关节软骨细胞和软骨下成骨细胞的调节参与了骨关节炎的病理生理过程，mTORC1信号通路介导了WNT1在骨关节炎病理生理中的作用。为了验证这一假设，该项目将利用多个遗传小鼠模型。具体目标1的目的是确定WNT1在骨性关节炎的病理生理学中的作用。具体目标2的目标是确定mTORC1在骨性关节炎的病理生理学中是WNT1功能的重要中介。这项研究的意义不仅在于确定新的分子和细胞串扰作为OA的病理生理学机制，而且还将确定促进OA进展的特定信号级联。因此，这项研究的结果将为开发OA治疗的治疗策略提供新的见解，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特殊设施，分子和人类遗传学系致力于为申请者提供最好的培训。完成这项研究还将为骨关节炎研究提供足够的关键技能和深入知识的培训，并将使申请者成为一名成功的独立研究者，专注于骨关节炎的病理生理机制。

 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.