Transcription factor Mohawk in tendon and ligament degeneration and regeneration

转录因子莫霍克在肌腱和韧带退化和再生中的作用

• 批准号: 8722781
• 负责人: HIROSHI ASAHARA
• 金额: $ 41.69万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8722781
• 关键词: Accounting; Address; Adenoviruses; Adult; Affect; Age; Aging; Aging-Related Process; Amino Acids; Anterior; Architecture; Arthritis; Biology; Birth; Cell Differentiation process; Cells; Chondrogenesis; Collagen Type I; Data; Dense Connective Tissue; Development; Disease; Enhancers; Extracellular Matrix; Fascicle; Fiber; Fibroblasts; Gene Expression; Gene Expression Microarray Analysis; Gene Targeting; Genetic; Genetic Transcription; Healed; High Prevalence; Homeobox Genes; Homeostasis; Human; In Vitro; Inflammatory; Injury; Interleukin-1; Joints; Knee Osteoarthritis; Knock-in Mouse; Knowledge; Laboratories; Lead; Ligaments; Limb Development; Maintenance; Mechanics; Mesenchymal Stem Cells; Modeling; Modification; Mohawk Indian; Molecular; Mus; Muscle; Natural regeneration; Phenotype; Population; Posterior Cruciate Ligament; Rattus; Risk Factors; Role; Rotator Cuff; Shoulder Pain; Site; Staging; Stimulus; Syndrome; System; Tendon Injuries; Tendon structure; Testing; Tissues; Venus; age related; aggrecan; base; bone; genome wide association study; healing; human tissue; improved; injured; ligament injury; member; novel; novel therapeutic intervention; polypeptide; progenitor; public health relevance; regenerative; repaired; response; scleraxis; tissue repair; transcription factor; triple helix

DESCRIPTION (provided by applicant): Tendons and ligaments are dense connective tissues of mesodermal origin, which connect muscles to bones or bone to bone, and transmit mechanical force. The extracellular matrix (ECM) consists mainly of collagen type 1, organized as triple-helix polypeptide chains, which unite into fibrils, fibers, fascicles, tertiary bundles, forming the tendon and ligament architecture. Damage to tendons and ligaments caused by overuse or injuries is not healed and rarely recovers completely. In addition, to injury, aging-related changes in cells and ECM of ligaments and tendons represent an important risk factor for the development of knee osteoarthritis or rotator cuff syndrome. Obstacles in the development of approaches to address tendon and ligament damage are partly due to the limited knowledge about mechanisms that regulate development, adult tissue homoeostasis and regenerative responses following injury. We recently identified Mohawk (Mkx) as a key regulator of tendon and ligament development. Mkx is a member of the Three Amino acid Loop Extension superclass of atypical homeobox genes. Mkx-/- mice had hypoplastic tendons throughout the body, clearly demonstrating an essential function of Mkx in tendon development. Importantly, Mkx is highly expressed in adult human and mouse tenocytes and ligament cells but its expression is decreased in aging or in arthritis-affected joints and in response to inflammatory stimuli such as interleukin-1. These observations support our hypothesis that Mkx is a central regulator of adult tendon and ligament homeostasis and that its suppression following injury or during aging and arthritis accounts for limited repair responses and leads to degenerative changes. To test this hypothesis and reveal the molecular mechanisms of Mkx to maintain and/or regenerate tendon/ligament, we will perform the following studies. Aim 1: Determine Mkx targets and functions in tendon/ligament cells during development and after birth. Aim 2: Analyze mechanisms controlling tendon/ligament specific expression of Mkx. Aim 3: Examine role of Mkx in tenogenic differentiation of mesenchymal stem cells and its potential to enhance repair or regeneration of tendon injuries. Feasibility of this project is based on availability of several genetically modified mouse lines, including conditional Mkx TG and KO mice; access to human ligament cells from a wide range of donors across the adult age spectrum and at various stages of ACL degeneration and multiple genome-wide screening systems. The findings from this study are expected to advance our current understanding of tendon and ligament biology and serve as a basis for the development of new therapeutic approaches for tendon and ligament injuries and diseases.

描述（由申请人提供）：肌腱和韧带是中胚层的密集结缔组织，它们将肌肉与骨骼或骨骼连接到骨骼，并传递机械力。细胞外基质（ECM）主要由1型胶原蛋白组成，该胶原蛋白以三螺旋多肽链的组织，将其团结成纤维，纤维，束，三级束，形成肌腱和韧带结构。因过度使用或受伤引起的肌腱和韧带的损害无法治愈，很少完全恢复。此外，对于损伤，韧带和肌腱与衰老相关的细胞和ECM的变化是膝关节骨关节炎或肩袖综合征发展的重要危险因素。解决肌腱和韧带损伤方法开发方法的障碍部分是由于对调节发育，成人组织同在的机制的知识有限，受伤后的成人组织同种异体和再生反应。我们最近将莫霍克族（MKX）确定为肌腱和韧带发育的关键调节剂。 MKX是非典型同源基因基因的三个氨基酸环延伸超类的成员。 MKX - / - 小鼠在整个身体中都有肌腱肌肌腱，清楚地表明了MKX在肌腱发育中的重要功能。重要的是，MKX在成年人类和小鼠弯曲细胞和韧带细胞中高度表达，但其表达在衰老或受关节感染的关节中降低，并响应炎性刺激（例如Interleuukin-1）。这些观察结果支持我们的假设，即MKX是成年肌腱和韧带稳态的中心调节剂，并且其受伤后的抑制作用或衰老和关节炎期间的抑制作用占维修的有限反应，并导致退化性变化。为了检验这一假设并揭示了MKX维持和/或再生肌腱/韧带的分子机制，我们将进行以下研究。 AIM 1：确定发育过程和出生后肌腱/韧带细胞中的MKX靶标和功能。 AIM 2：分析控制MKX的肌腱/韧带特异性表达的机制。 AIM 3：检查MKX在间充质干细胞的肾脏分化中的作用及其增强肌腱损伤修复或再生的潜力。该项目的可行性基于几种基因修饰的小鼠系的可用性，包括条件MKX TG和KO小鼠。从成人年龄谱的广泛供体以及ACL变性和多个全基因组筛查系统的各个阶段的供体访问人类韧带细胞。这项研究的发现有望提高我们对肌腱和韧带生物学的当前理解，并作为开发肌腱和韧带损伤和疾病的新治疗方法的基础。