Investigating the role of the RNA binding protein HuR in musculoskeletal development and disease

研究 RNA 结合蛋白 HuR 在肌肉骨骼发育和疾病中的作用

• 批准号: MR/N011333/1
• 负责人: Simon Tew
• 金额: $ 52.86万
• 依托单位: University of Liverpool
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FN011333%2F1
• 关键词: Investigating; role; RNA; binding; protein

Age-associated diseases of the musculoskeletal system carry a heavy socio-economic burden, which is set to increase as life expectancy increases. Many of these diseases affect bone or cartilage in the joints, and lead to immobility and pain. This project will determine a molecular mechanism that can control cartilage formation and has strong relevance to the processes that affect cartilage in diseases of old age such as osteoarthritis. The central molecule of interest that is involved in the processes to be examined is a protein called HuR. It regulates the function of genes by controlling the destruction of an important functional molecule called mRNA. Importantly, HuR is widespread in the body and performs a number of critical roles in many tissues.There is good evidence that HuR has important functions in cartilage but a study to fully define these roles has yet to be conducted. Therefore, the project's first aim will be to fully characterise the distribution and timing of HuR production in the developing skeleton, using the mouse as a model. Then, using a genetically modified mouse that we have recently developed in which HuR levels can be knocked out specifically in cartilage tissues, we will examine the effect that loss of HuR has on cartilage development as well as on knee joint degeneration in adult animals.A further aim of the project is to determine the mechanisms affected by HuR in a cell culture model of cartilage development. We will use state-of-the-art gene sequencing technology and subsequent molecular analysis methods to identify the mRNAs regulated by HuR in cartilage cells and how this is occurring. The technologies used in this part of the project have the added benefit of defining how gene regulation that controls cartilage formation is affected at different tiers of control in a far greater level of detail than has previously been attempted.To investigate the translational opportunities of these findings we will determine how inhibiting the functions of HuR can alter the generation of bone and cartilage tissue by adult human stem cells. These studies will allow the use of reagents that we already know directly affect HuR function, offering a valid approach for tissue regeneration when employed in laboratory-based skeletal tissue engineering.

与肌肉骨骼系统相关的疾病带来沉重的社会经济负担，随着预期寿命的增加，这种负担肯定会增加。这些疾病中的许多会影响关节中的骨或软骨，并导致不动和疼痛。该项目将确定一种可以控制软骨形成的分子机制，并与影响老年疾病（如骨关节炎）中软骨的过程密切相关。参与待检测过程的中心分子是一种称为HuR的蛋白质。它通过控制一种叫做mRNA的重要功能分子的破坏来调节基因的功能。重要的是，HuR在体内广泛分布，并在许多组织中发挥重要作用。有充分的证据表明，HuR在软骨中具有重要功能，但尚未进行充分定义这些作用的研究。因此，该项目的第一个目标将是使用小鼠作为模型，在开发中的骨架中完全模拟HuR生产的分布和时间。然后，利用我们最近开发的基因修饰小鼠，在软骨组织中特异性地敲除HuR水平，我们将研究HuR缺失对软骨发育以及成年动物膝关节退化的影响。本项目的进一步目的是在软骨发育的细胞培养模型中确定HuR影响的机制。我们将使用最先进的基因测序技术和随后的分子分析方法来鉴定软骨细胞中HuR调控的mRNA以及这是如何发生的。在这个项目的这一部分所使用的技术有额外的好处，定义如何控制软骨形成的基因调控是在一个更大的水平比以前尝试的细节在不同层次的控制受到影响。调查这些发现的转化机会，我们将确定如何抑制HuR的功能可以改变成人干细胞的骨和软骨组织的生成。这些研究将允许使用我们已经知道的直接影响HuR功能的试剂，当用于基于实验室的骨骼组织工程时，为组织再生提供有效的方法。