Mechanisms of Primary Cilia Regulating Tendon Enthesis Development and Regeneration

初级纤毛调节肌腱附着点发育和再生的机制

基本信息

批准号：
10707864
负责人：
Fei Fang
金额：
$ 58.44万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10707864
关键词：
Ablation Acute Adult Affect Age Architecture Biochemical Biological Assay Biology Biomechanics Cartilage Cell Transplantation Cell surface Cells Chondrocytes Chondrogenesis Cicatrix Cilia Clinical Data Deterioration Development Disease Environment Epiphysial cartilage Erinaceidae Event Failure Fibrocartilages General Population Genetic Transcription Hypertrophy Immunohistochemistry Impairment In Situ Hybridization Injury Knockout Mice Knowledge Label Length Maintenance Mammalian Cell Mechanical Stimulation Mechanics Mediating Medical Modeling Molecular Mus Muscle Natural regeneration Neonatal Older Population Operative Surgical Procedures Organelles Outcome Pain Pathogenesis Pathology Pathway interactions Patients Pilot Projects Population Process Protocols documentation Regenerative capacity Regulation Reporter Reporting Role Rotator Cuff Shoulder Shoulder Pain Signal Transduction Sports Stimulus Tendon structure Testing Therapeutic Tissues Transgenic Mice United States Work biomechanical test bone bone fracture repair cost disability experience healing improved in vivo injured mechanical force mechanical load mechanical properties mechanical signal mechanotransduction mineralization mouse model muscle regeneration novel novel therapeutic intervention pharmacologic postnatal programs repaired response rotator cuff tear single molecule single-cell RNA sequencing smoothened signaling pathway soft tissue stem cell function stem cell population stem cells stemness therapeutically effective transcriptomics

项目摘要

PROJECT SUMMARY 40% of the population over the age of 60 experiences a rotator cuff tear. The high failure rates of rotator cuff tear after surgical repair or non-surgical treatment make it a major clinical challenge. The outcome failures accompany the formation of scar tissues at the tendon-to-bone insertion (tendon enthesis) with disorganized architecture and deteriorated function. Development of effective therapeutics has been hampered by limited knowledge of enthesis development biology and mechanobiology and an incomplete understanding of endogenous mechanisms governing enthesis pathogenesis and healing. To bridge this knowledge gap, the current proposal seeks to elucidate how tendon enthesis responds to its mechanical and biochemical environment during development and healing processes. It is known that a combination of mechanical force and distinct pathways, including hedgehog (Hh) signaling, drive enthesis formation, promote remodeling of mature enthesis, and affect enthesis healing. Recently, our studies have indicated that the primary cilium, a solitary antenna protruding from mammalian cell surface, potentially functions as a hub for mechanotransduction and Hh signaling. Building on our previous work, the objective of this proposal is to gain a mechanistic understanding of the role of primary cilia in concentrating and synchronizing mechanical and Hh signals during enthesis development and healing. To achieve this objective, we will determine identities and activities of ciliated enthesis cells during enthesis development and mechanical adaptation (Specific Aim 1) and evaluate the regenerative capacity of ciliated enthesis cells for improving enthesis healing (Specific Aim 2). The approaches we will use include cilia-labeled and cilia-deleted transgenic mouse models, different established loading models, cell transplantation, and transcriptomics analysis, combined with structural, compositional, and biomechanical evaluation assays. At the conclusion of this project, we expect to identify new cilia-regulated mechano- transduction pathways during in vivo enthesis mechanical adaptation and suggest novel mechanisms by which cilia convert mechanical cues to cellular signaling events. The new findings of the role of primary cilia in enthesis healing will guide the development of novel pharmacological and mechanobiology therapeutics for treating rotator cuff tears.

项目概要 60 岁以上的人群中有 40% 经历过肩袖撕裂。肩袖撕裂的失败率很高手术修复或非手术治疗后使其成为重大的临床挑战。结果失败伴随着肌腱与骨骼插入处（肌腱附着点）处疤痕组织的形成，且组织混乱建筑和退化的功能。有效治疗方法的开发受到有限的阻碍对附着点发育生物学和机械生物学的了解以及对控制附着点发病机制和愈合的内源性机制。为了弥合这一知识差距，目前的提案旨在阐明肌腱附着点如何对其机械和生化反应做出反应发育和愈合过程中的环境。众所周知，机械力和不同的途径，包括刺猬 (Hh) 信号传导、驱动着丝点形成、促进成熟的重塑附着点，影响附着点愈合。最近，我们的研究表明，初级纤毛是一种孤立的纤毛。从哺乳动物细胞表面伸出的天线，有可能作为机械传导的枢纽嗯发出信号。基于我们之前的工作，该提案的目标是获得机械理解初级纤毛在附着过程中集中和同步机械信号和 Hh 信号的作用发展和治愈。为了实现这一目标，我们将确定纤毛附着点的身份和活动附着点发育和机械适应期间的细胞（具体目标 1）并评估再生能力纤毛附着点细胞改善附着点愈合的能力（具体目标 2）。我们将使用的方法包括纤毛标记和纤毛缺失的转基因小鼠模型、不同建立的加载模型、细胞移植和转录组学分析，结合结构、成分和生物力学评估分析。在该项目结束时，我们期望找到新的纤毛调节机制体内附着机械适应过程中的转导途径，并提出了新的机制纤毛将机械信号转化为细胞信号事件。初级纤毛在着丝过程中作用的新发现治愈将指导新型药理学和机械生物学疗法的开发肩袖撕裂。