Coordination Funds

协调基金

• 批准号: 407145811
• 负责人: Professor Dr. Bent Brachvogel
• 金额: --
• 依托单位: Klinik und Poliklinik für Kinder- und Jugendmedizin
• 依托单位国家: 德国
• 项目类别: Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/407145811?language=en
• 关键词: Coordination; Funds

The FOR2722 research unit has identified novel functions of the ECM across musculoskeletal tissues and gained novel mechanistic insights into connective tissue disorders. Our new discoveries underscore the interdependency between metabolism, secretion pathway-dependent extracellular matrix (ECM) formation and its cellular recognition and recycling. We now hypothesize that a fine-tuned balance between inside-out ECM production and outside-in ECM recognition and remodelling defines musculoskeletal integrity and function across tissues. In the next funding period, the overarching goal of the FOR2722 will be to understand how changes in ECM production, recognition and remodelling can affect the function of musculoskeletal tissues and cause chronic connective tissue disorders. In our four research areas, we will focus on key fundamental questions in musculoskeletal ECM homeostasis emerging from our research in the first funding period: Metabolism - Through which metabolic signalling mechanisms can mtRC dysfunction be translated into disturbed vesicle-mediated ECM secretion and assembly processes in cartilage? Which mechanisms regulate bioavailability and cellular responses of asprosins? Biosynthesis and assembly - To which extent and through which mechanisms are the distinct muscle cell populations affected by mutated collagen VI and how do they contribute to myopathies? How do collagens XII and XIV organize the ECM and the presentation of ECM-encoded bioactive signals to drive neuromuscular development, regeneration and degeneration processes? Cellular communication - Does integrin α11 constitute an invadopodia-associated sensing element of cartilage damage in Fibroblast-like synoviocytes during rheumatoid arthritis and is it linked to their transformation by transmitting signals through collagen fragments into cell-specific alterations that in a perpetuating loop favour further cartilage destruction? How do extracellular microfibrillar networks participate in cell-ECM communication at musculoskeletal junctions? Degradation - How does deficiency or overexpression of Plastin3 disrupt fundamental cellular processes dependent on F-actin dynamics and vesicle trafficking resulting in bone and cartilage ECM-related diseases? Which factors are involved in the onset of osteogenesis imperfecta and can they be targeted to develop suitable new therapies for non-classical osteogenesis patients? How is the reciprocal communication between cells and their ECM fine-tuned at the mechanistic level? It is our overarching goal is to understand how these molecular processes contribute to the onset and progression of musculoskeletal disease and to translate this newly generated knowledge into additional therapeutic options.

FOR 2722研究单位已经确定了ECM在肌肉骨骼组织中的新功能，并获得了对结缔组织疾病的新机制见解。我们的新发现强调了代谢，分泌途径依赖性细胞外基质（ECM）形成及其细胞识别和回收之间的相互依赖性。我们现在假设，由内而外的ECM生产和由外而内的ECM识别和重塑之间的微调平衡定义了整个组织的肌肉骨骼完整性和功能。在下一个资助期内，FOR 2722的总体目标将是了解ECM产生、识别和重塑的变化如何影响肌肉骨骼组织的功能并导致慢性结缔组织疾病。在我们的四个研究领域中，我们将专注于我们在第一个资助期的研究中出现的肌肉骨骼ECM稳态的关键基本问题：代谢-通过代谢信号机制可以将mtRC功能障碍转化为受干扰的囊泡介导的ECM分泌和软骨组装过程？哪些机制调节阿司匹林的生物利用度和细胞反应？生物合成和组装-在何种程度上和通过何种机制是不同的肌肉细胞群体受到突变的胶原VI和他们如何有助于肌病？胶原蛋白XII和XIV如何组织ECM和ECM编码的生物活性信号的呈现，以驱动神经肌肉发育，再生和变性过程？细胞通讯-整合素α11是否构成类风湿性关节炎期间成纤维细胞样滑膜细胞中软骨损伤的侵袭足相关传感元件，是否通过将信号通过胶原片段传递到细胞特异性改变而与其转化相关，这些改变在永久循环中有利于进一步的软骨破坏？细胞外微纤维网络如何参与肌肉骨骼连接处的细胞-ECM通讯？降解-Plastin 3的缺乏或过度表达如何破坏依赖于F-肌动蛋白动力学和囊泡运输的基本细胞过程，从而导致骨和软骨ECM相关疾病？哪些因素参与了骨生成障碍的发生，它们是否可以成为针对非经典骨生成患者开发合适的新疗法的目标？细胞与其ECM之间的相互通信是如何在机制层面上进行微调的？我们的总体目标是了解这些分子过程如何促进肌肉骨骼疾病的发生和进展，并将这些新产生的知识转化为其他治疗方案。