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

利用遗传学、细胞和基质的相互作用，深入了解肌肉骨骼健康和肌肉骨骼疾病的新疗法

• 批准号: MR/Y030419/1
• 负责人: Dominic Furniss
• 金额: $ 542.06万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FY030419%2F1
• 关键词: Harnessing; interplay; genetics; cells; matrix

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.

自二十年前人类基因组项目完成以来，我们进入了遗传发现的黄金时代。我们对遗传学的理解决定了我们的外表，思维方式以及我们一生中的疾病越来越全面。这个黄金时代有望通过对常见疾病的新疗法进行彻底改变医学，但这种诺言尚未完全实现。特别是，肌肉骨骼（MSK）系统（如骨关节炎和腕管综合征）非常常见的疾病，与任何其他疾病类别相比，造成骨关节炎和腕管综合症会导致多年的残疾和疼痛。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使人衰弱状况的理解和治疗。 MSK系统描述了负责运动的身体的骨骼，关节，软骨和软组织。 MSK系统的疾病负责大量降低生活质量和身体局限性，但是对MSK疾病的研究数量并不能反映出这一重要性，部分原因是由于缺乏资金，部分原因是历史上很难研究MSK疾病。在我们的研究上，我们的研究来确定这些障碍的范围，以确定这些障碍的情况，以确定这些障碍，以至于跨越了四个跨越的概述，以至于跨越了四个跨度，以至于四个概述，以至于四四范围的差异，以使四个跨度的差异避免了四个方面的疾病，从而避免了四个常见的疾病，从而使他们的差异四四个疾病，从而避免了四个疾病，从而使四范围内的差异逐渐消失，以确定四范围的差异。除了止痛药，物理疗法和严重疾病的手术（骨关节炎，腕管综合症，肩膀冷冻和Dupuytren病）之外。我们将使用手术中收集的废物组织来查看细胞的内部生物学以及构成受该疾病影响的组织（称为基质）的其他分子（称为基质）。然后，我们将能够将遗传变异与生物学功能的变化联系起来。这将创造一个主要的资源，世界其他MSK研究人员可以在其工作中使用。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于潜在的药物靶标。在我们研究的第二部分中，我们将对实验室的组织进行实验，以定义干扰这些途径对细胞和组织如何表现的影响。我们还将构建特殊的机器人“生物反应器” - 机器人，以模仿这些MSK组织在体内经历的物理力。这将使我们能够查看疾病基因与体内的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提供足够的证据，以便我们在未来5 - 10年内开始对这些疾病的新药物进行人体试验。我们的研究团队由外科医生，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年内开始对新的MSK疾病治疗进行人体试验。我们非常适合实现该项目的目标，因为我们以前在确定目前正在进行临床试验的手动骨关节炎方面取得了成功。这项研究将使我们能够将研究扩展到其他几个条件，并最终开始实现遗传学的希望以改善人口的健康。我们站在医学上的重大飞跃的门槛上。我们的工作植根于对遗传学的复杂理解，渴望实现遗传学的长期承诺 - 重塑健康和保健景观的希望。随着我们更深入地研究这项激动人心的努力，我们对将研究转化为有效的解决方案很乐观，从而改善公共卫生并减轻MSK疾病的负担。