Role of inorganic polyphosphate in articular cartilage homeostasis

关节软骨是一种覆盖在滑膜关节骨表面的软组织。这种承重组织可以实现低摩擦运动，并通过关节分配传递的力。软骨的完整性是通过严格调控的机制来维持的，这些机制平衡了组织的分解和新合成的生物分子的替代(动态平衡)。随着关节内生物或机械环境的变化，这两个过程之间的长期失衡与骨关节炎(OA)的发病有关。骨关节炎是一组以软骨进行性退化为特征的衰弱关节疾病，影响着300多万加拿大人。在我的学术生涯中，我在材料工程和基质生物学方面积累了跨学科的专业知识，因为它与软骨生物学和修复有关。作为渥太华大学的一名新教员，我将建立一个研究项目，专注于阐明调控软骨内稳态的动态细胞-组织相互作用。了解这些控制机制不仅将提供更完整的生理过程图景，使组织能够维持其在体内的功能，还将开发下一代生物材料，使细胞与控制特定生物过程的指导性环境相连接。使用这种治疗方法恢复健康的软骨将改善医疗实践，恢复生活质量，并减轻加拿大和世界范围内OA患者的社会和经济负担。在这项申请中，要求为这项研究计划的第一阶段提供资金，旨在评估无机聚磷酸盐(PP)--存在于关节软骨细胞周围基质中的一种生物分子--调节内稳态的假设。鉴于它参与了一系列哺乳动物组织中越来越多的基本过程，因此迫切需要提高我们对PP生物学的理解。在此，我们建议在我们先前工作的基础上证明PP在关节软骨中的合成代谢作用，以确定其对合成代谢和分解代谢过程之间的平衡的影响程度，并确定其在响应机械刺激的组织重塑中的作用。最后，我们将探索PP影响的信号通路，以更好地了解软骨细胞与其细胞周围环境之间的动态相互作用。这笔资金也将在我的指导下支持4HQP的发展。通过这些多学科项目的工作，研究生将获得各种技术技能，并获得批判性思维和创造力的机会，这将为他们在生物医学工程领域的继续职业生涯做好准备。

Articular cartilage is a soft tissue that covers the surfaces of bones in synovial joints. This load-bearing tissue enables low friction movement and distributes forces transmitted through the joint. Cartilage integrity is maintained by tightly regulated mechanisms that balance the breakdown of the tissue and its replacement with newly synthesized biomolecules (homeostasis). Prolonged imbalance between these two processes in response to a changing biological or mechanical environment in the joint has been associated with the onset of osteoarthritis (OA), a group of debilitating joint diseases characterized by the progressive degradation of cartilage that affects more than 3 million Canadians. Over the course of my academic career, I have developed cross-disciplinary expertise in materials engineering and matrix biology as it pertains to cartilage biology and repair. As a new faculty member at the University of Ottawa, I will establish a research program focused on elucidating the dynamic cell-tissue interactions regulating cartilage homeostasis. Understanding these control mechanisms will not only provide a more complete picture of physiological processes that allow tissues to maintain their functions in the body, but also to develop next-generation biomaterials that interface cells with instructive environments, which control specific biological processes. Restoring healthy cartilage using such treatments would improve healthcare practice, as well as recovering quality of life and alleviating the social and economic burdens of OA sufferers in Canada and worldwide.In this application, funding is requested for the first stage of this research program, aimed at evaluating the hypothesis that inorganic polyphosphate (PP), a biomolecule present in the pericellular matrix of articular cartilage, regulates homeostasis. In light of its involvement in a mounting number of fundamental processes in a range of mammalian tissues, there is a critical need to improve our understanding of PP biology. Here, we propose to build on our previous work demonstrating the anabolic effects of PP in articular cartilage to establish the extent of its effects on the balance between anabolic and catabolic processes and to determine its role in tissue remodeling in response to mechanical stimulation. Finally, we will explore the signaling pathways impacted by PP to produce a better understanding of the dynamic interactions between chondrocytes and their pericellular environment.This funding will also support the development of 4 HQP under my guidance. Through their work on these multidisciplinary projects, the graduate students will acquire a variety of technical skills and be provided with opportunities for critical thinking and creativity that will prepare them for a continued career in biomedical engineering.