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.

FOR2722研究小组已经确定了跨肌肉骨骼组织的ECM的新功能，并获得了结缔组织疾病的新机制见解。我们的新发现强调了代谢、分泌途径依赖的细胞外基质（ECM）形成与其细胞识别和循环之间的相互依赖性。我们现在假设，在由内而外的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，mtRC功能障碍可以转化为软骨中囊泡介导的ECM分泌和组装过程的紊乱？哪些机制调节阿斯普蛋白酶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和通过何种机制受到突变的胶原VI的影响，它们是如何导致肌病的？XII和XIV胶原如何组织ECM和ECM编码的生物活性信号的呈现来驱动神经肌肉的发育、再生和退化过程？细胞通讯-整合素α11是否构成类风湿关节炎期间成纤维细胞样滑膜细胞软骨损伤的侵入性相关传感元件？它是否与它们通过胶原片段向细胞特异性改变传递信号的转化有关，这种转变在一个永久的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-缺乏或过度表达Plastin3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？哪些因素与成骨不全症的发生有关，这些因素是否可以针对非典型成骨患者开发合适的新疗法？细胞和它们的ECM之间的相互交流是如何在机制水平上微调的？我们的首要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额外的治疗选择。