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（由申请人提供）：我们之前已经表明，TGFβ 信号传导是肌腱细胞命运的关键调节剂：TGFβ 信号传导是肌腱标记物的有效诱导剂，肢芽间质中 TGFβ 信号传导的破坏导致肌腱发育失败。该提议基于对 TGFβ 信号在肌腱发育后期的作用的观察，我们发现使用 TGFβ 受体 (TβR2) 破坏肌腱细胞中的 2 型 TGFβ 受体 (TβR2)。 ScxCre 肌腱删除剂导致出生后早期肌腱退化，随后出现退化过程，我们发现肌腱细胞去分化并不是由于 TGFβ 信号传导的内在缺失。孤立的肌腱细胞斑块中的 TβR2 没有类似的作用，因此我们发现 TGFβ 信号传导的丧失会导致肌腱中的细胞-细胞或细胞-基质相互作用，从而导致肌腱细胞破坏分化和肌腱退化。主要方向，第一个目标是确定是否存在一个发育时间窗口，在该时间窗口中 TGFβ 信号传导的破坏将导致肌腱退化，并开发更有限的表型模型，从而能够跟踪退化过程的全部范围和将其开发为肌腱病分析系统。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所必需的关键特征。最后，在第三个目标中，我们分析其作用。基于显示 TGFβ 和激活素信号之间协同相互作用的初步结果，我们对激活素信号在此过程中的作用进行了研究。