Sex Differences in Tendon Growth and Remodeling

肌腱生长和重塑的性别差异

• 批准号: 9235619
• 负责人: Christopher L Mendias
• 金额: $ 9.99万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9235619
• 关键词: 3' Untranslated Regions; Adult; Ankle; Applications Grants; Binding; Biology; Cell Culture Techniques; Cells; Cellular biology; Clinic; Development; Disease; Embryo; Embryonic Development; Exercise; Extracellular Matrix; Failure; Fibroblasts; Future; Gene Expression; Genes; Goals; Healed; Health; Human; In Vitro; Injury; Insulin-Like Growth Factor I; Introns; Knowledge; Laboratories; Lead; Life; Limb Bud; Limb structure; Link; Maintenance; Measures; Mechanics; Messenger RNA; MicroRNAs; Mission; Modification; Molecular; Molecular Biology; Molecular Genetics; Molecular Profiling; Mus; Musculoskeletal System; Natural regeneration; Pain; Pathogenesis; Pathway interactions; Patients; Physiological Adaptation; Physiology; Play; Property; Protocols documentation; Public Health; Quality of life; Regulation; Role; Sex Characteristics; Signal Pathway; Stress; Tendinopathy; Tendon Injuries; Tendon structure; Testing; Tissues; Training Programs; Transgenic Mice; Translating; Translations; Wild Type Mouse; Work; base; disability; embryo tissue; healing; histological studies; improved; in vivo; injured; insight; interdisciplinary approach; knock-down; postnatal; prevent; repaired; research study; response; restoration; scleraxis; tendon development; transcription factor; translational study; treadmill training

DESCRIPTION (provided by applicant): Our purpose is to gain a greater understanding of the basic cellular and molecular mechanisms that lead to tendinopathies and to translate these studies to the clinic. Tendon diseases can be painful, debilitating and significantly detract from the quality of one's life. Much of what we know about tendon fibroblast cell biology comes from in vitro cell culture studies or descriptive histological studies of diseased and healthy tissue. There has been a lack of in vivo, mechanism driven studies that combine contemporary molecular biology and genetics with precise tissue mechanics and functional measures. The long-term goal of this project is to better understand tendon fibroblast biology in the context of injury and disease, and to improve the treatment of tendinopathies. For many tissues in the body, the genes that control embryonic tissue development are also important in the repair and regeneration of adult tissues. Scleraxis is a bHLH transcription factor that is critical for the embryonic development of limb tendons, but little is known about scleraxis function in adult tendons. Our overall hypotheses are that scleraxis is important for the adaptation of tendons to mechanical loading, scleraxis is regulated by TGF-ß and IGF-1 signaling pathways, and that dysregulation of scleraxis is a central factor in the development of tendinosis. These hypotheses are rigorously tested in three Specific Aims that use a multidisciplinary approach involving a combination of molecular biology and tissue mechanics experiments in adult wild type mice (ScxWT), adult transgenic mice with a postnatal inducible knockdown of scleraxis (ScxKD), and in cultured primary tendon fibroblast cells from humans and mice. These studies will provide important insight into adult tendon fibroblast physiology, and lay the groundwork for future translational studies focused on scleraxis to improve the treatment of patients suffering from tendinopathies.

描述（由申请人提供）：我们的目的是更好地了解导致肌腱病的基本细胞和分子机制，并将这些研究转化为临床。肌腱疾病可能会带来疼痛、使人衰弱并严重降低人们的生活质量。我们对肌腱成纤维细胞生物学的了解大部分来自体外细胞培养研究或患病和健康组织的描述性组织学研究。缺乏将当代分子生物学和遗传学与精确的组织力学和功能测量相结合的体内机制驱动研究。该项目的长期目标是更好地了解损伤和疾病背景下的肌腱成纤维细胞生物学，并改善肌腱病的治疗。对于体内的许多组织来说，控制胚胎组织发育的基因对于成体组织的修复和再生也很重要。 Scleraxis 是一种 bHLH 转录因子，对于肢体肌腱的胚胎发育至关重要，但人们对成年肌腱中的 scleraxis 功能知之甚少。我们的总体假设是巩膜对于肌腱适应机械负荷很重要，巩膜受 TGF-β 和 IGF-1 信号通路调节，巩膜失调是肌腱变性发展的核心因素。这些假设在三个特定目标中经过严格测试，这些目标使用多学科方法，包括在成年野生型小鼠（ScxWT）、出生后诱导性硬化症敲低的成年转基因小鼠（ScxKD）以及来自人类和小鼠的培养的原代肌腱成纤维细胞中进行分子生物学和组织力学实验相结合。这些研究将为成人肌腱成纤维细胞生理学提供重要的见解，并为未来以硬化症为重点的转化研究奠定基础，以改善肌腱病患者的治疗。