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

随着人口日益老龄化，肥胖的流行导致活动能力下降，老年人的体力活动增加，肌肉骨骼疾病和疾病不断增加。骨的愈合潜力在不同的患者群体中差异很大，但对于内源性愈合过程如何因年龄、代谢状态或个体的免疫经历而改变，人们缺乏充分的了解。该合作研究中心旨在揭示骨再生成功与失败之间的基本机制。由于骨是人体中少数具有无疤痕愈合能力的组织之一，因此它是了解内源性愈合一般原理的理想模型系统，这也与其他组织的再生过程有关。骨愈合是由细胞自组织发起的，引导再生过程贯穿所有连续的再生阶段。骨再生的早期阶段对于长期愈合的成功至关重要，但在这些非常早期的阶段已经开始延迟愈合或不愈合。所有由细胞自组织驱动的再生级联反应的核心是：(1)控制良好的局部炎症反应，(2)平衡良好的营养供应和消耗，以及(3)通过力传递和传感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骨。为了证明这一假设，我们想要了解这些关键治疗机制之间的相互依赖关系，迄今为止，这些机制只从一维的角度进行了研究。本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)在健康老龄化过程中如何调整它们的相互依赖关系，使再生在原则上保持可能；(3)这三种关键机制如何受到与延迟或非愈合状况相关的不同压力源的挑战。在这个合作研究中心的12年期间，我们将在开始时集中精力了解这三种关键愈合机制之间的相互依赖关系。在第二个资助期内，我们的目标是了解压力源对三个关键愈合机制相互依赖的影响。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赖性，特别是在具有挑战性的临床环境中受损的愈合级联。我们将在临床前和男性首次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.