Wnt7a-Mediated Competence to Resist Osteoarthritis Progression

Wnt7a 介导的抵抗骨关节炎进展的能力

• 批准号: 10350647
• 负责人: Li Zeng
• 金额: $ 58.8万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-15 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10350647
• 关键词: Aging; Automobile Driving; Bioluminescence; Cartilage; Cartilage Matrix; Cells; Chondrocytes; Competence; Data; Degenerative polyarthritis; Disease; Disease Progression; Dose; Economic Burden; Ectopic Expression; Equilibrium; Family; Fluorescence; GDF5 gene; Generations; Genes; Goals; Grant; Heterogeneity; Human; Image; Imaging technology; Immune; Individual; Infiltration; Inflammation; Inflammatory; Interleukin-1 beta; Joints; Link; Maintenance; Matrix Metalloproteinases; Medial meniscus structure; Mediating; Messenger RNA; Modeling; Molecular Profiling; Mus; Pain; Pathogenesis; Pathway interactions; Persons; Population; Population Sizes; Proteins; Regulation; Resistance; Resolution; Risk Factors; Role; Sampling; Severities; Signal Transduction; Societies; Specimen; Stimulus; Technology; Testing; Time; Tissues; WNT Signaling Pathway; Work; articular cartilage; base; competence factor; conditional knockout; cytokine; design; effective therapy; high risk; improved; individual response; insight; joint destruction; joint injury; loss of function; microCT; novel; nuclear factors of activated T-cells; optimal treatments; preservation; receptor; response; second harmonic; stem

Abstract: Wnt7a-mediated competence to resist osteoarthritis progression Osteoarthritis (OA) is a highly prevalent and debilitating disease that currently has no effective therapy. OA has many risk factors, such as joint injury and aging. However, many people with these risk factors do not develop OA or develop it to a lesser extent. Individual responses to the same treatment are often also highly variable, hampering the testing of therapy in a reasonable-sized population. Thus, there is an urgent need to understand the basis for the diverse manifestations of OA. One driving factor of OA is proposed to be local inflammation. As prolonged inflammation elicits catabolic changes in the joint, the ability of each individual to resist inflammation could be directly linked to the trajectory of disease progression. Identifying factors that provide the competence to resist inflammation may be key to elucidating the cause of OA progression in individuals. Our long-term goal is to investigate OA pathogenesis to improve its treatment. The goal of this grant is to investigate the competence to resist inflammation and joint destruction conferred by an underexplored molecule (Wnt7a) from the Wnt signaling family. This proposal is based on our study that showed a striking negative-exponential relationship between Wnt7a and catabolic genes in individual human cartilage specimens. When Wnt7a expression was below a certain threshold, the samples were almost always of OA background, as if low levels of Wnt7a signify a higher risk of OA. In this way, Wnt7a may be a key factor associated with OA variability. Ectopic expression of Wnt7a under normal conditions did not impact cartilage matrix levels, but strongly halted joint destruction in experimental OA, suggesting that Wnt7a provided the joint with a certain ability to resist OA. Thus, we hypothesize that the level of Wnt7a within articular cartilage determines the competence against inflammation and impacts the trajectory of OA in each individual, forming the basis for OA variability. This hypothesis will be tested in two Specific Aims by 1) investigating whether Wnt7a alters the course of inflammation and the trajectory of cartilage loss and joint destruction in OA and 2) identifying downstream pathways and upstream regulators of Wnt7a. We will use gain- and loss-of function approaches on mouse OA and human cartilage specimens. The novelty of this study lies in the concept of Wnt7a as a competence factor for OA resistance in individuals to explore the mechanism of heterogeneity in OA, and in the use of advanced imaging technologies to test these concepts. These studies will define the role of Wnt7a in curtailing prolonged inflammation and the propensity for degenerative changes in OA. Furthermore, it will identify fundamental mechanisms for enhancing or preserving endogenous Wnt7a function in cartilage for joint protection. Thus, this work will provide important mechanistic insights into OA progression and its variability and the design of strategies to treat this disease.

翻译后摘要：Wnt7a介导的能力，以抵抗骨关节炎的进展 骨关节炎（OA）是一种高度流行和衰弱的疾病，目前没有有效的治疗方法。OA有 许多风险因素，如关节损伤和衰老。然而，许多有这些危险因素的人不会发展 或发展到较小的程度。个体对相同治疗的反应往往也是高度可变的， 妨碍在合理规模的人群中进行治疗试验。因此，迫切需要了解 OA的各种表现的基础。OA的一个驱动因素被认为是局部炎症。 由于长时间的炎症刺激了关节的分解代谢变化，每个人抵抗关节炎的能力都降低了。 炎症可能与疾病进展的轨迹直接相关。确定提供 抵抗炎症的能力可能是阐明个体中OA进展原因的关键。 我们的长期目标是研究OA的发病机制，以改善其治疗。该补助金的目标是 研究抵抗炎症和关节破坏的能力， 分子（Wnt7a）来自Wnt信号传导家族。这项建议是基于我们的研究，显示了一个惊人的 个体人软骨中Wnt7a和分解代谢基因之间的负指数关系 标本当Wnt7a表达低于某一阈值时，样品几乎总是OA的 背景，就好像低水平的Wnt7a意味着更高的OA风险。因此，Wnt7a可能是一个关键因素， 与OA变异性相关。正常条件下Wnt7a的异位表达不影响软骨 基质水平，但在实验性OA中强烈阻止了关节破坏，表明Wnt7a提供了关节 具有一定的抗OA能力。因此，我们假设关节软骨中Wnt7a的水平 决定对抗炎症的能力并影响每个个体中OA的轨迹， 形成OA变异性的基础。这一假设将在两个具体目标中进行检验，1）调查 Wnt7a是否改变OA中的炎症过程以及软骨损失和关节破坏的轨迹 和2）鉴定Wnt7a的下游途径和上游调节子。我们将使用增益和损失 功能的方法对小鼠OA和人软骨标本。这项研究的新奇在于， Wnt7a作为个体OA抵抗的能力因子的概念，以探讨 在OA的异质性，并在使用先进的成像技术来测试这些概念。这些研究 将确定Wnt7a在减少长期炎症和退行性变化倾向中的作用 在OA。此外，它将确定增强或保留内源性Wnt7a的基本机制， 保护关节软骨的功能。因此，这项工作将提供重要的机械见解OA 进展及其变异性和治疗这种疾病的策略的设计。