Maintenance and Regulation of Tendon and Ligament Maturation by TGFbeta Signaling

通过 TGFbeta 信号传导维持和调节肌腱和韧带成熟

• 批准号: 9252382
• 负责人: RONEN SCHWEITZER
• 金额: $ 30.08万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9252382
• 关键词: Activin Receptor; Activins; Acute; Affect; Animal Model; Animals; Birth; Cells; Characteristics; Chronic; Collagen; Cytoskeleton; Degenerative Disorder; Dependence; Development; Disease; Embryonic Development; Environment; Etiology; Evaluation; Failure; Gene Expression; Genetic; Genetic Models; Human; Incidence; Inflammation; Injury; Light; Limb Bud; Maintenance; Mesenchyme; Modeling; Molecular; Molecular Profiling; Morbidity - disease rate; Morphology; Movement; Musculoskeletal; Musculoskeletal System; Pain; Pathologic; Pathology; Phenotype; Play; Population; Predisposing Factor; Process; Recruitment Activity; Regulation; Role; Signal Transduction; Stem cells; Structure; Systems Analysis; Tendinopathy; Tendon structure; Testing; Time; Tissue Sample; Tissues; Transforming Growth Factor beta; base; fascinate; ligament development; motor impairment; mouse development; mutant; postnatal; public health relevance; pup; receptor; tendon development; transcriptome sequencing

 DESCRIPTION (provided by applicant): We have previously shown that TGFβ signaling is a key regulator of the tendon cell fate: TGFβ signaling is a potent inducer of tendon markers and disruption of TGFβ signaling in limb bud mesenchyme resulted in failure of tendon development. This proposal is based on observations regarding the role of TGFβ signaling in later stages of tendon development. We find that disrupting the type 2 TGFβ receptor (TβR2) in tenocytes using the ScxCre tendon deletor resulted in tendon degeneration in early postnatal stages. Interestingly, embryonic development of the tendons was not affected and the tendons developed a robust and organized collagen matrix, but in early stages of postnatal development the movement of TβR2;ScxCre pups was perturbed and their tendons showed gradual loss of tendon markers followed by degenerative processes. Moreover, we find that tenocyte dedifferentiation was not due to an intrinsic loss of TGFβ signaling, since loss of the TβR2 in isolated patches of tenocytes did not have a similar effect. We therefore hypothesize that loss of TGFβ signaling results in disruptions to cell-cell or cell-matrix interactions in tendons leading o tenocyte dedifferentiation and tendon degeneration. The proposed project follows these observations in three major directions, the first aim is to determine if there is a developmental time window in which disruption of TGFβ signaling will lead to tendon degeneration and to develop more limited model of the phenotype that will enable following the full scope of the degenerative process and developing it as a system for analysis of tendinopathy. In the second aim we will investigate the cellular and molecular changes in the mutant tendons to identify the key features essential for maintenance of the tendon cell fate. Finally, in the third aim we analyze the role of activin signaling in this process based on preliminary results that show synergistic interactions between TGFβ and activin signaling.

 描述(申请人提供)：我们先前已经证明转化生长因子β信号是肌腱细胞命运的关键调节因子：转化生长因子β信号是肌腱标志物的有效诱导者，肢体芽间充质中转化生长因子β信号的干扰导致肌腱发育失败。这一建议是基于对转化生长因子β信号在肌腱发育后期阶段的作用的观察。我们发现，使用ScxCre肌腱去除器破坏肌腱细胞中的2型转化生长因子β受体(TβR2)会导致出生后早期的肌腱退变。有趣的是，肌腱的胚胎发育没有受到影响，肌腱形成了坚固而有组织的胶原基质，但在出生后发育的早期阶段，TβR2；ScxCre幼鼠受到干扰，其肌腱标志逐渐丢失，随后出现退化过程。此外，我们发现腱细胞的去分化不是由于转化生长因子β信号的内在缺失，因为分离的腱细胞斑块中TβR2的缺失没有类似的影响。因此，我们假设转化生长因子β信号的丢失导致肌腱细胞-细胞或细胞-基质相互作用的中断，导致肌腱细胞去分化和肌腱退变。该项目从三个主要方向跟踪这些观察，第一个目标是确定转化生长因子β信号的中断是否存在导致肌腱退变的发育时间窗口，并开发更有限的表型模型，使其能够跟踪退变过程的全部范围，并将其发展为肌腱病的分析系统。在第二个目标中，我们将研究突变肌腱的细胞和分子变化，以确定维持肌腱细胞命运的关键特征。最后，在第三个目标中，我们根据初步结果分析了激活素信号在这一过程中的作用，初步结果表明转化生长因子β和激活素信号之间存在协同作用。