Harnessing the interplay of genetics, cells, and matrix, to deliver insights into musculoskeletal health and new therapies in musculoskeletal disease

自从20年前人类基因组计划完成以来，我们进入了基因发现的黄金时代。我们对基因如何决定我们的长相、思维方式以及我们一生中会得什么疾病的理解越来越全面。这个黄金时代有望带来医学革命，为常见疾病提供新的治疗方法，但这一承诺尚未完全实现。特别是，非常常见的肌肉骨骼（MSK）系统疾病，如骨关节炎和腕管综合征，导致的残疾和疼痛比任何其他疾病类别都要长。我们的研究将解决这个问题，利用遗传学来提高我们对这些衰弱疾病的理解和治疗。MSK系统描述了人体负责运动的骨骼、关节、软骨和软组织。MSK系统的疾病是导致长时间生活质量下降和身体限制的原因，但对MSK疾病的研究数量并没有反映出这种重要性，部分原因是缺乏资金，部分原因是历史上研究MSK疾病在技术上一直很困难。在我们的研究中，我们计划通过定义基因变异来克服这些障碍，这些变异使我们容易患上四种非常常见的致残MSK疾病，目前除了止痛药、物理疗法和严重疾病（骨关节炎、腕管综合征、肩周炎和Dupuytren病）的手术之外，没有其他治疗方法。我们将使用手术中收集的废弃组织来观察细胞的内部生物学，以及构成组织的其他分子（称为基质），这些分子受到疾病的影响。这样我们就能将基因变异与生物功能的变化联系起来。这将为世界各地的其他MSK研究人员创造一个可以在他们的工作中使用的主要资源。我们将仔细解释这些实验的结果，以确定哪些基因和途径最适合作为潜在的药物靶点。在我们研究的第二部分，我们将在实验室中对组织进行实验，以确定干扰这些途径对细胞和组织行为的影响。我们还将建造特殊的机器人“生物反应器”——模仿这些MSK组织在体内所经历的物理力量的机器人。这将使我们能够看到疾病基因和体内机械力之间的相互作用。我们希望这些分析的结果将为我们在未来5-10年内开始对这些疾病的新药进行人体试验提供足够的证据。我们的研究团队由外科医生、内科医生、遗传学专家、生物学家、实验室科学家和数据专家组成。凭借我们的专业知识和经验，我们希望在未来5-10年内开始新的MSK疾病治疗的人体试验。我们非常适合实现这个项目的目标，因为我们之前已经成功地确定了一种治疗手部骨关节炎的新方法，目前正在进行临床试验。这项研究将使我们能够将我们的研究扩展到其他几种情况，并最终开始实现遗传学改善人口健康的承诺。我们正站在医学科学重大飞跃的起点上。我们的工作植根于对遗传学的复杂理解，渴望实现遗传学长期以来的承诺——重塑健康和保健的前景。随着我们对这一激动人心的努力的深入研究，我们对将我们的研究转化为有效的解决方案，以提高公众健康并减轻MSK疾病的负担持乐观态度。

Since the completion of the Human Genome Project two decades ago, we have entered a golden age of genetic discovery. Our understanding of how genetics determines how we look, how we think, and what diseases we get during our lives is increasingly comprehensive. This golden age promised to revolutionise medicine, with new treatments for common diseases, but this promise has not yet been fully realised. In particular, very common diseases of the musculoskeletal (MSK) system such as osteoarthritis and carpal tunnel syndrome, cause more years of disability and pain than any other disease class. Our research will address this issue, using genetics to improve our understanding and treatment of these debilitating conditions. The MSK system describes the bones, joints, cartilage, and soft tissues of the body that are responsible for movement. Diseases of the MSK system are responsible for extensive periods of reduced quality of life and physical limitations, but the amount of research into MSK disease does not reflect this importance, partly because of a lack of funding, and partly because historically it has been technically difficult to study MSK diseases.In our study, we plan to overcome these hurdles by defining the genetic variations that predispose us to four very common, disabling, MSK conditions that have no current treatments beyond painkillers, physiotherapy, and surgery for severe disease (osteoarthritis, carpal tunnel syndrome, frozen shoulder, and Dupuytren's disease). We will use waste tissue collected at surgery to look at the internal biology of the cells, and other molecules that make up the tissue (called the matrix), that are affected by the disease. We will then be able to link the genetic variations to changes in biological function. This will create a major resource that other MSK researchers around the world can use in their work. We will carefully interpret the results of these experiments to decide which genes and pathways are best suited as potential drug targets.In the second part of our study, we will perform experiments on tissues in the lab to define the effects of interfering with these pathways on how the cells and tissues behave. We will also build special robotic "bioreactors" - robots to mimic the physical forces that these MSK tissues experience in the body. This will allow us to look at the interaction between disease genes and mechanical forces in the body. We hope that the results of these analyses will provide enough evidence for us to begin human trials of new medicines in these diseases over the next 5-10 years. Our research team is made up of surgeons, medical doctors, genetics experts, biologists, lab scientists, and data specialists. With our combined expertise and experience, we hope to start human trials of new MSK disease treatments within the next 5-10 years. We are uniquely suited to achieving the aims of this project, as we have previously achieved success in identifying a new treatment in hand osteoarthritis, that is currently undergoing clinical trials. This study will enable us to expand our research to several other conditions and finally begin to deliver on the promise of genetics to improve the health of the population. We stand at the threshold of a significant leap in medical science. Our work, rooted in the intricate understanding of genetics, aspires to fulfil the long-standing promise of genetics - the promise to reshape the landscape of health and wellness. As we work deeper into this exciting endeavour, we are optimistic about translating our research into effective solutions that enhance public health and reduce the burden of MSK diseases.