Regulation of Tendon Induction and Formation By TGFbeta Signaling

TGFbeta 信号传导对肌腱诱导和形成的调节

• 批准号: 7496484
• 负责人: RONEN SCHWEITZER
• 金额: $ 32.45万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-15 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7496484
• 关键词: Address; Anatomy; Biomedical Engineering; Cartilage; Cell Line; Cells; Cephalic; Clinical; Commit; Dependence; Development; Differentiation and Growth; Embryo; Event; Fibroblast Growth Factor; Generations; Genes; Growth; Infection; Laboratories; Lead; Limb structure; Location; Mesenchymal; Modeling; Molecular; Mus; Muscle; Muscle Development; Musculoskeletal System; Numbers; Organ; Organ Culture Techniques; Paper; Phenotype; Play; Regulation; Role; Shapes; Signal Transduction; Smad Proteins; Smad protein; Staging; Stem cells; System; Tail; Tendon Injuries; Tendon structure; Tissues; Transforming Growth Factor beta; bone; early embryonic stage; in utero; in vivo; mutant; progenitor; receptor; research study; scleraxis; synergism; tissue culture; transcription factor; transmission process

DESCRIPTION (provided by applicant): A functional musculoskeletal system depends upon the transmission of force from muscle to bone, thus requiring the coordinated development of muscle, cartilage and tendon. Little however, is known about the cellular and molecular aspects of tendon formation. Progress unraveling the signals that direct mesenchymal cells to become tenocytes is of particular importance in elucidation of the early events that shape the organization and coordinated growth of the musculoskeletal system. Moreover, a tendon inducing activity may be of considerable clinical importance both for improvements in the treatment of tendon injuries and in bioengineering efforts to induce tendon formation from stem cells. The recent finding that Scleraxis (Scx) a bHLH transcription factor is a unique marker of tenocytes and tendon progenitors facilitated studies of tendon development and a number of subsequent studies have implicated FGF signaling in the induction of tendon progenitors. Dramatic results in our laboratory now demonstrate an even more profound role for TGF( signaling in tendon induction and differentiation. Embryos doubly mutant for the TGF(2 and TGF(3 genes develop limbs in which no tendons can be detected. Moreover, TGF( signaling acts as a potent inducer of Scx, in organ culture and in tissue culture experiments, significantly exceeding the extent and intensity of Scx induction by FGF signaling in similar experiments. We propose to explore TGF( role in tendon formation in three separate groups of experiments. The first aim will address the hypothesis that all tendon tissues depend on TGF( signaling. The phenotype in axial and cranial tendons will be evaluated in TGF(2 & 3 mutants and in mutants for a TGF( receptor (TGF(RII), in which all TGF( signaling is eliminated. We will further study the onset of the tendon phenotype in these mutants to establish the stage in which TGF( signaling is essential for tendon formation. The second aim will be to address the hypothesis that TGF( signaling is essential for later aspects of tendon formation as well. Inducible elimination of TGF(RII will enable exploration of later roles for TGF( signaling and establish if tendons are generated from a committed pool of early progenitors or through continuous recruitment of tendon cells by TGF( signaling to support tendon growth. Finally, the mechanism of Scx induction by TGF( signaling will be explored in tissue culture and in vivo; the activities of TGF( and FGF signaling will be compared and the possibilities of synergism or interdependence between these two signaling cascades will be explored using a combination of specific antagonists and mutant tissues. In addition, TGF( will be applied in utero using a retroviral system to evaluate the capacity of the cells induced by TGF( signaling to go beyond expression of Scx and cause the formation of ectopic or expanded tendons.

描述（由申请人提供）：功能性肌肉骨骼系统取决于从肌肉到骨骼的力传递，因此需要肌肉、软骨和肌腱的协调发展。然而，人们对肌腱形成的细胞和分子方面知之甚少。阐明引导间充质细胞变成肌腱细胞的信号的进展对于阐明塑造肌肉骨骼系统的组织和协调生长的早期事件特别重要。此外，肌腱诱导活性对于改善肌腱损伤的治疗和诱导干细胞形成肌腱的生物工程努力可能具有相当大的临床重要性。最近发现 Scleraxis (Scx) 是一种 bHLH 转录因子，是肌腱细胞和肌腱祖细胞的独特标记物，这促进了肌腱发育的研究，并且许多后续研究表明 FGF 信号传导与肌腱祖细胞的诱导有关。我们实验室的戏剧性结果现在证明 TGF( 信号传导在肌腱诱导和分化中具有更深远的作用。TGF(2 和 TGF(3 基因) 双突变的胚胎发育出无法检测到肌腱的肢体。此外，TGF( 信号传导在器官培养和组织培养实验中充当 Scx 的有效诱导剂，显着超过 Scx 诱导的程度和强度 类似实验中的 FGF 信号传导。我们建议在三组不同的实验中探索 TGF( 在肌腱形成中的作用。第一个目标将解决所有肌腱组织都依赖于 TGF( 信号传导) 的假设。轴肌腱和颅肌腱的表型将在 TGF(2 和 3 突变体以及 TGF( 受体 (TGF(RII)) 突变体中进行评估，其中所有 TGF( 信号传导） 被淘汰。我们将进一步研究这些突变体中肌腱表型的开始，以确定 TGF( 信号传导对于肌腱形成至关重要的阶段。第二个目标是解决 TGF( 信号传导对于肌腱形成的后期方面也至关重要的假设。诱导消除 TGF(RII 将使探索 TGF( 信号传导的后期作用成为可能，并确定肌腱是否是从早期的承诺库中产生的) 最后，将在组织培养和体内探索 TGF( 信号传导诱导 Scx 的机制；比较 TGF( 和 FGF 信号传导的活性，并使用特定拮抗剂和突变组织的组合来探索这两种信号传导级联之间协同或相互依赖的可能性。 此外，TGF(将使用逆转录病毒系统应用于子宫内，以评估TGF(信号传导超出Scx表达并导致异位或扩张肌腱形成的细胞能力。