The regulation of collagen (I) homotrimer synthesis and its role in musculoskeletal dysfunction

胶原蛋白（I）同源三聚体合成的调节及其在肌肉骨骼功能障碍中的作用

• 批准号: MR/R00319X/1
• 负责人: Elizabeth Laird
• 金额: $ 71.1万
• 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: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FR00319X%2F1
• 关键词: regulation; collagen; homotrimer; synthesis; its

Musculoskeletal diseases such as osteoarthritis, osteoporosis and soft-tissue injuries together with tissue and organ fibrosis impose a huge healthcare burden, particularly in the ageing population. Therefore understanding the regulation of abnormal collagen (I) synthesis and its role in bone and joint function is of critical importance in order to develop strategies to target these debilitating diseases.Collagen (type I) is the most abundant structural protein in the body and is the major component of bone and joint tissues. Type I collagen forms fibres that surround cells and make tissues resilient to mechanical loading. The natural form of type I collagen can be degraded and reformed by cells using biological enzymes and this process allows skeletal tissues to adapt to changes in mechanical loading. When the tissue structure is inadequate to resist external loads, tissue injury including fractures and ruptures can occur. In the general population such problems are manifested as diseases including osteoporosis (weak bone), osteoarthritis (cartilage loss and bone overgrowth) and soft tissue injuries. Over-production of type I collagen (termed fibrosis) furthermore restricts tissue function leading to disability and increased morbidity and mortality. Genetic and biochemical studies have found that an abnormal form of type I collagen, termed collagen (I) homotrimer, is present in both degenerative and fibrotic diseases. This abnormal collagen alters the biophysical properties of collagen fibrils and is resistant to enzymatic breakdown. Collagen (I) homotrimer may therefore affect the ability of tissues to respond to changing mechanical loads and to counteract fibrosis. The aim of this project is to determine whether relative collagen (I) mRNA (COL1A1 and COL1A2) levels direct collagen (I) homotrimer synthesis and if collagen (I) homotrimer produces an inadequate but persistent fibrillar matrix that leads to age-related musculoskeletal disease and fibrosis, or whether pathology could be accounted for by cellular stress caused by over-production of the collagen alpha-1(I) chain.A complex series of cellular interactions normally results in collagen (I) heterotrimer but this project will test the hypothesis that increased levels of the COL1A1 mRNA overwhelms the ability of the cells to control heterotrimer synthesis and results in the concurrent production of abnormal collagen (I) homotrimer. Cells contain an elaborate system of controls that regulate gene activity and protein production and small RNA molecules termed microRNAs appear to be particularly important. MicroRNAs bind to the mRNA intermediates (between gene activity and protein production) often decreasing their effectiveness. miR-133 is known to target COL1A1 rather than COL1A2 and is less abundant in several fibroses. This project will test how increasing or decreasing miR-133 activity affects collagen (I) homotrimer synthesis and will determine whether it could be a novel target for musculoskeletal and fibrotic diseases.To reveal how collagen fibrils containing collagen (I) homotrimer affect musculoskeletal tissues a comprehensive analysis of the structural and biomechanical alterations in hard and soft collagenous tissues will be performed in mice lacking the COL1A2 gene. Preliminary phenotyping data (IMPC) indicates that these mice have abnormal bone morphology and defects in soft collagenous tissues. A well-characterised osteogenesis imperfecta mouse model ('oim') that produces collagen (I) homotrimer along with truncated alpha-2(I) chains will be used as a control. The apparently more severe oim phenotype may result from cellular stress, therefore cellular stress will be evaluated in genetically manipulated cell cultures and mouse tissues. Cellular stress can be targeted by several pharmaceuticals so could potentially be reduced to help treat these diseases.

肌肉骨骼疾病，例如骨关节炎，骨质疏松症和软组织损伤，以及组织和器官纤维化，造成了巨大的医疗保健负担，尤其是在老龄化的人群中。因此，了解异常胶原蛋白（I）合成及其在骨骼和关节功能中的作用对于制定靶向这些使人衰弱的疾病的策略至关重要。Collagen（I型）是体内最丰富的结构蛋白，并且是骨和关节组织的主要成分。 I型胶原蛋白形成围绕细胞的纤维，使组织能够韧性，可抵御机械负荷。 I型胶原蛋白的自然形式可以通过生物学酶通过细胞降解和改革，此过程允许骨骼组织适应机械负荷的变化。当组织结构不足以抵抗外部载荷时，可能会发生包括裂缝和破裂在内的组织损伤。在普通人群中，这种问题表现为包括骨质疏松症（骨骼弱），骨关节炎（软骨丧失和骨过度生长）和软组织损伤的疾病。 I型胶原蛋白（称为纤维化）的过度生产还限制了组织功能导致残疾，发病率和死亡率增加。遗传和生化研究发现，称为胶原蛋白（I）同型二聚体的I型胶原蛋白异常形式存在于退化性和纤维化疾病中。这种异常的胶原蛋白改变了胶原纤维的生物物理特性，并且对酶促分解具有抗性。因此，胶原蛋白（i）同构元可能会影响组织对机械负荷变化和抵消纤维化反应的能力。该项目的目的是确定相对胶原蛋白（i）mRNA（col1a1和col1a2）水平直接胶原蛋白（i）同构二聚体合成以及胶原蛋白（i）是否会产生不足但持续的纤维基质导致过度相关的肌肉疾病的纤维化症状，还是持续的纤维基质产生的纤维化症状，是否会导致纤维化症状，是否导致了纤维化的纤维化，这是否会导致纤维化的纤维化，这是否导致了纤维化的症状。 collagen alpha-1(I) chain.A complex series of cellular interactions normally results in collagen (I) heterotrimer but this project will test the hypothesis that increased levels of the COL1A1 mRNA overwhelms the ability of the cells to control heterotrimer synthesis and results in the concurrent production of abnormal collagen (I) homotrimer.细胞包含一个详尽的控制系统，该系统调节基因活性和蛋白质产生，而称为microRNA的小RNA分子似乎尤其重要。 microRNA与mRNA中间体（在基因活性和蛋白质产生之间）结合，通常会降低其有效性。已知miR-133靶向COL1A1而不是COL1A2，并且在几种纤维纤维中较少。该项目将测试MIR-133活性增加或减少如何影响胶原蛋白（i）同型二聚体合成，并将确定它是否可以成为肌肉骨骼和纤维化疾病的新颖靶标。在缺乏COL1A2基因的小鼠中进行。初步表型数据（IMPC）表明这些小鼠在软胶原组织中具有异常的骨形态和缺陷。特征良好的成骨不完美的小鼠模型（'oim'）将使用胶原蛋白（i）同型二聚体以及截短的alpha-2（i）链，将用作对照。明显更严重的OIM表型可能是由细胞应激引起的，因此将在遗传操纵的细胞培养物和小鼠组织中评估细胞应激。细胞应激可以由几种药物靶向，因此可能会减少以帮助治疗这些疾病。

项目成果

Collagen (I) homotrimer potentiates the osteogenesis imperfecta (oim) mutant allele and reduces survival in male mice.

• DOI: 10.1242/dmm.049428
• 发表时间: 2022-09-01
• 期刊: Disease models & mechanisms
• 影响因子: 4.3

Collagen (I) homotrimer potentiates the osteogenesis imperfecta (oim) mutant allele and reduces survival in male mice

• DOI: 10.1101/2020.07.13.198283
• 发表时间: 2020-07
• 期刊: Disease Models & Mechanisms
• 影响因子: 4.3
• 作者: K. Lee;Lisa Rambault;George Bou-Gharios;P. Clegg;R. Akhtar;G. Czanner;R. J. van ‘t Hof;E. Canty-Laird

Identification and Characterization of Canine Ligament Progenitor Cells and Their Extracellular Matrix Niche

• DOI: 10.1021/acs.jproteome.8b00933
• 发表时间: 2019-03-01
• 期刊: JOURNAL OF PROTEOME RESEARCH
• 影响因子: 4.4
• 作者: Lee, Katie J.;Comerford, Eithne J.;Canty-Laird, Elizabeth G.
• 通讯作者: Canty-Laird, Elizabeth G.