Regulation of Adult Tendon Growth and Regeneration by Scleraxis

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。肌腱疾病可能会令人痛苦，使人虚弱，并显著降低一个人的生活质量。我们对肌腱成纤维细胞生物学的大部分了解来自于体外细胞培养研究或疾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、机制驱动的研究。该项目的长期目标是在损伤和疾病的背景下更好地了解肌腱成纤维细胞生物学，并改进肌腱疾病的治疗。对于体内的许多组织来说，控制胚胎组织发育的基因在成年组织的修复和再生过程中也很重要。肌腱硬化轴是一种bHLH转录因子，对肢体肌腱的胚胎发育至关重要，但对其在成年肌腱中的作用知之甚少。我们的总体假设是，硬化症对于肌腱对机械负荷的适应是重要的，硬化症由转化生长因子-β调节。和IGF-1信号通路，而硬化轴的失调是肌腱病发生的中心因素。这些假说在三个特定的目标上得到了严格的验证，这三个目标使用了一种多学科的方法，涉及分子生物学和组织力学实验的组合，在成年野生型小鼠(ScxWT)、出生后可诱导巩膜轴基因敲除的成年转基因小鼠(ScxKD)以及培养的人和鼠的原代肌腱成纤维细胞中。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，并为今后以硬化症为重点的转化性研究改善肌腱病患者的治疗奠定基础。

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-? 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.