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: 9064632
• 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/9064632
• 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 Transcription; Healed; Health; High Prevalence; Homeobox Genes; Homeostasis; Human; In Vitro; Inflammatory; Injury; Interleukin-1; Joints; Knee Osteoarthritis; Knock-in Mouse; Knockout Mice; 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; Regenerative response; Risk Factors; Role; Rotator Cuff; Shoulder Pain; Site; Staging; Stimulus; Syndrome; System; Tendon Injuries; Tendon structure; Testing; Tissues; Venus; age related; aggrecan; base; bone; genetic approach; genome-wide analysis; healing; human tissue; improved; injured; ligament development; ligament injury; member; novel; novel therapeutic intervention; polypeptide; progenitor; repaired; response; scleraxis; tendon development; 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起源的致密结缔组织，将肌肉与骨骼或骨骼与骨骼连接起来，并传递机械力。细胞外基质 (ECM) 主要由 1 型胶原组成，组织为三螺旋多肽链，结合成原纤维、纤维、束、三级束，形成肌腱和韧带结构。由于过度使用或受伤而造成的肌腱和韧带损伤无法治愈，并且很少能完全恢复。此外，除了损伤之外，韧带和肌腱的细胞和 ECM 的老化相关变化也是膝骨关节炎或肩袖综合征发生的重要危险因素。开发解决肌腱和韧带损伤方法的障碍部分是由于对调节发育、成体组织稳态和损伤后再生反应的机制了解有限。我们最近确定莫霍克 (Mkx) 是肌腱和韧带发育的关键调节因子。 Mkx 是非典型同源框基因三氨基酸环延伸超类的成员。 Mkx-/- 小鼠全身肌腱发育不全，清楚地表明 Mkx 在肌腱发育中的重要功能。重要的是，Mkx 在成人和小鼠的肌腱细胞和韧带细胞中高度表达，但其表达在衰老或关节炎影响的关节中以及对白细胞介素 1 等炎症刺激的反应中降低。这些观察结果支持我们的假设，即 Mkx 是成人肌腱和韧带稳态的中央调节器，并且其在受伤后或衰老和关节炎期间的抑制导致有限的修复反应并导致退行性变化。为了检验这一假设并揭示 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。目标 1：确定发育期间和出生后肌腱/韧带细胞中的 Mkx 目标和功能。目标 2：分析控制 Mkx 肌腱/韧带特异性表达的机制。目标 3：检查 Mkx 在间充质干细胞肌腱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多种转基因小鼠品系的可用性，包括条件性 Mkx TG 和 KO 小鼠；获得来自不同成人年龄范围和 ACL 变性不同阶段的广泛捐赠者的人类韧带细胞和多个全基因组筛选系统。这项研究的结果预计将增进我们目前对肌腱和韧带生物学的理解，并为开发肌腱和韧带损伤和疾病的新治疗方法奠定基础。