SFB 1444: Directed Cellular Self-Organisation for Advancing Bone Regeneration

由于肥胖症的流行导致行动不便，以及日益老龄化的人口中老年人体力活动增加，肌肉骨骼疾病和障碍不断增加。骨的愈合潜力在不同的患者组中差异很大，但对于内源性愈合过程是如何因个体的年龄、新陈代谢状态或免疫经验而改变的了解很少。该合作研究中心旨在揭示区分骨再生成败的基本机制。由于骨是体内为数不多的具有无疤痕愈合能力的组织之一，因此它是一个理想的模型系统，可以理解内源性愈合的一般原理，这也与其他组织的再生过程有关。骨愈合是由细胞自组织启动的，在所有连续的再生阶段引导再生过程。骨再生的早期阶段对于长期的愈合成功是必不可少的，但在这些非常早期的阶段也已经开始延迟愈合或骨不愈合。由细胞自组织驱动的所有再生级联反应的核心是(1)良好控制的局部炎症反应，(2)良好平衡的营养供应和消费，以及(3)通过力传递和感知进行结构良好的基质重组。这是三个关键的机制，需要密切协调，以实现成功的内源性组织再生。为了证明这一假设，我们想要了解这些关键的愈合机制之间的相互依存关系，到目前为止，这些机制只从一维的角度进行了研究。这个CRC的目的是揭示(1)这三个关键机制之间的相互作用是如何被控制和调节的；(2)它们之间的相互依赖在健康衰老过程中是如何被调节的，从而使再生在原则上仍然是可能的；以及(3)三个关键机制中的每一个如何受到与延迟或无法愈合的条件相关的不同应激源的挑战。在这个合作研究中心12年的时间里，我们将从一开始就专注于理解这三个关键治愈机制之间的相互依存关系。在第二个资助期内，我们的目标是了解应激源对三个关键康复机制的相互依存关系的影响。最后，在第三个资助期，我们的目标是控制和指导三个关键机制及其相互依存关系，特别是在具有挑战性的临床环境中受损的愈合级联。我们将在临床前和首例临床研究中验证我们对“控制”机制的理解，从而为个性化治疗方法奠定基础。

Musculoskeletal diseases and disorders are on the continuous rise due to the epidemic of obesity resulting in reduced mobility, and the increased physical activity of the elderly in an increasingly aging population. The healing potential of bone varies greatly in the different patient groups, but there is a substantial lack of understanding how the endogenous healing processes are altered due to age, metabolic status or immune experience of the individuals. This Collaborative Research Center aims to unravel the basic mechanisms that differentiate between success and failure in bone regeneration. Since bone is one of the few tissues in the body that has the general capability of scar-less healing resulting in complete functional and structural reconstitution it is an ideal model system to understand the general principals of endogenous healing, which is relevant also for regeneration processes of other tissues. Bone healing is initiated by cellular self-organisation that guides the regenerative processes throughout all consecutive regeneration phases. The early phases of bone regeneration are essential for the long-term healing success, but also delays of healing or non-unions are already initiated during these very early stages. Central to all regenerative cascades driven by cellular self-organisation are (1) a well-controlled local inflammatory response, (2) well-balanced nutrition supply and consumption, and (3) a well-structured matrix re-organization by force transmission and sensing. These are the three key mechanism that need to be closely coordinated to achieve successful endogenous tissue regeneration in bone. To prove this hypothesis, we want to understand the interdependencies between these key mechanisms of healing, which have only been studied from a one-dimensional perspective so far. The aim of this CRC is to reveal (1) how the interplay between these three key mechanisms is controlled and regulated; (2) how their interdependencies are adjusted during healthy aging so that regeneration remains - in principle – possible; and (3) how each of the three key mechanisms are challenged by distinct stressors that are associated with delayed or non-healing conditions. Over the 12-year period of this Collaborative Research Center, we will concentrate in the beginning on the understanding of the interdependencies between these three key mechanisms of healing. Within the second funding period, we aim to understand the effect of stressors on the interdependencies of the three key mechanisms of healing. Finally, in the third funding period we aim at controlling and steering the three key mechanisms and their interdependencies, specifically in impaired healing cascades of challenged clinical settings. We will validate our understanding of the “control” mechanism in both pre-clinical and first-in-men clinical studies and thereby lay the foundation for personalized therapeutic approaches.