Coordination Funds

FOR2722研究单位已经确定了细胞外基质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的机制见解。我们的新发现强调了新陈代谢、分泌途径依赖的细胞外基质(ECM)的形成及其细胞识别和循环之间的相互依存关系。我们现在假设，由内而外的ECM产生和由外而内的ECM识别和重塑之间的微调平衡定义了肌肉骨骼的完整性和跨组织的功能。在下一个资助期，FOR2722的首要目标将是了解细胞外基质的产生、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，我们将重点关注我们在第一个资助期的研究中出现的肌肉骨骼ECM动态平衡的关键基础问题：代谢-通过什么代谢信号机制将mtRC功能障碍转化为囊泡介导的软骨ECM分泌和组装过程紊乱？哪些机制调节Asprosins的生物利用度和细胞反应？生物合成和组装--不同的肌肉细胞群在多大程度上受到V型胶原突变的影响，并通过哪些机制受到影响，它们是如何促进肌病的？XII和XIV胶原蛋白如何组织细胞外基质和细胞外基质编码的生物活性信号的呈现，以驱动神经肌肉的发育、再生和退化过程？细胞通讯-整合素α11是否构成类风湿性关节炎成纤维细胞样滑膜细胞中软骨损伤的跨膜相关感知元件，以及它是否通过胶原片段传递信号进入细胞特异性改变，从而有利于进一步的软骨破坏，从而与其转化有关？细胞外微纤维网络如何参与肌肉骨骼连接处的细胞-细胞外基质通讯？降解-Plastin3的缺乏或过表达如何扰乱依赖F-肌动蛋白动力学和囊泡运输的基本细胞过程，从而导致骨和软骨细胞外基质相关疾病？哪些因素参与了成骨不全的发生，它们能否有针对性地为非经典成骨患者开发合适的新疗法？细胞和它们的细胞外基质之间的相互沟通是如何在机制层面上进行微调的？我们的首要目标是了解这些分子过程如何有助于肌肉骨骼疾病的发生和发展，并将这一新产生的知识转化为其他治疗方案。

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.