Understanding the activities of connective tissue fibroblasts during muscle formation towards understanding disease and engineering muscle tissue

影响肌肉骨骼（MSK）系统正常功能的疾病很常见，可能由出生缺陷、运动损伤、创伤、疾病、正常磨损和年龄相关疾病引起。总之，MSK疾病对卫生保健系统和护理人员造成重大负担，并导致生产力损失。不断扩大的老龄化人口意味着MSK疾病的病例数量及其带来的负担在未来将急剧增加。我们的目标是应对MSK疾病的挑战，并为提高生活质量，健康和生产力的健康益处做出贡献。拟议的工作包统一在解决肌肉组织如何构建以及如何在疾病中被破坏的基本问题上。了解组织是如何构建的对于开发组织工程策略和再生疗法至关重要，这些策略和疗法可以取代因创伤、磨损或疾病而丢失的组织。组织形成的破坏会导致肢体出生缺陷，了解什么以及什么时候发生了错误对于诊断，管理和治疗制度至关重要。我们的目标是通过研究和理解支撑组织构建的分子和细胞机制，我们可以开发复制和利用这些过程进行组织工程和再生疗法的方法。我们选择将重点放在肢体肌肉上，将其作为一个实验上易于处理的系统，并且具有明确的临床适用性。工具已经可以在培养皿中制造肌纤维，我们对肌肉前体向肌纤维的终末分化的进展如何进行调节有了很好的理解和控制。然而，我们对肌纤维如何组织成组织块的理解非常有限，因此，我们距离能够设计功能性肌肉组织还有很长的路要走。肌肉组织不仅仅是肌肉纤维的集合。肌束是肌纤维和不规则结缔组织（ICT）成纤维细胞的复合物，它们是功能性肌束的高度组织化结构的关键组成部分。虽然ICT的重要性已经得到了很好的证实，但人们对这些细胞的作用以及它们在肌肉形成和修复过程中的作用知之甚少。ICT及其衍生物，例如肌肉筋膜）是肌肉组织的重要组成部分。学习以及如何复制或模仿ICT的活动是任何肌肉工程战略的关键。我们专注于填补目前在理解ICT功能方面的空白，开发研究ICT功能的新方法，以及开发工程肌肉组织的新方法。我们正在采取新的，无毛，无毛学科的方法来确定控制肌肉形成和修复的机制，并开发工具来研究这些过程，并将我们的发现转化为MSK疾病的新治疗方法。我们还将免费制作一个可访问的人类胚胎肢体发育参考数据库，将为教育工作者，研究人员和临床医生创建永久资源。这一资源将有助于解释先天性肢体畸形的确切起源，并揭示在人类胚胎发育过程中新生组织被破坏时的敏感窗口。

Diseases that effect proper functioning of the musculoskeletal (MSK) system are common and can arise from birth defects, sports injuries, trauma, disease, normal wear-and-tear and age-related diseases. Together, MSK diseases contribute a significant burden on health care systems, carers and lead to lost productivity. The expanding ageing population means the number of cases of MSK disease, and the burden this imposes, will expand dramatically in the future. We aim to address the challenges of MSK disease and contribute to health benefits that will enhance quality of life, health and productivity.The proposed work packages are unified in tackling the fundamental question of how are muscle tissues built and how this can become disrupted in disease. Understanding how tissues are built is essential to develop tissue engineering strategies and regenerative therapies that can replace tissue lost through trauma, wear-and-tear or disease. Disruption of tissue formation produces limb birth defects and understanding what and when events have gone wrong is critical for diagnosis, management and treatment regimes. Our aim is by studying and understanding the molecular and cellular mechanisms that underpin how tissues are built, we can develop ways to replicate and harness these processes for tissue engineering and regenerative therapies.We have chosen to focus on limb muscles as an experimentally tractable system and one that has clear clinical applicability. Tools are already available to make muscle fibres in a dish and we have a good understanding and control over how the progression of terminal differentiation of muscle precursors to myofibres is regulated. We have very poor understanding, however, of how myofibres are organised into blocks of tissue and as a result we are still a long way from being able to engineer functional muscle tissue.Muscle tissue is not simply a collection of muscle fibres. A muscle bundle is a composite of muscle fibres and irregular connective tissue (ICT) fibroblasts, which are critical constituents of the highly organised architecture of a functional muscle bundle. Although the importance of ICT is well established, very little is known about what these cells do and how they act during muscle formation and repair. ICT and its derivatives, e.g. muscle fascia) is an essential component of muscle tissue. Learning and how to replicate or mimic the activities of ICT is an essential in any strategy to engineer muscle. We are focussing on filling the current gap in understanding of the functions of ICT, in developing novel approaches to study ICT function and in developing novel approaches to engineer muscle tissue.We are taking novel, mullti-disciplinary approaches to identify the mechanisms controlling muscle formation and repair and in developing tools to study these process and translate our findings into new treatments for MSK diseases.We will also produce a freely accessible, reference database of human embryonic limb development that will create a permanent resource for educators, researchers and clinicians. This resource will help explain the precise origins of congenital limb abnormalities and reveal the sensitivity window when nascent tissues have been disrupted during human embryonic development.