Mechanisms of TGF-b regulation of muscle differentiation

描述：（由申请人提供）：本提案的总体目标是 建立生理学相关模型，研究TGF-β信号如何通过 Smad通路调节骨骼肌的终末分化 细胞项目的第一部分旨在确定机制的特点 通过TGF-β激活的Smads抑制MyoD家族的功能， 肌源性bHLH转录因子并抑制肌肉分化。 具体来说，这些实验将扩展我们最初的发现， 对于Smad 3在肌肉特异性转录的抑制中， 潜在机制以及每种潜在机制的作用 肌生成过程中TGF-β拮抗作用的机制。第二 本建议的目的是评估物理和功能的相互作用 Smads和MEF 2家族转录因子之间的关系，并阐明 这种相互作用对肌源性分化影响。最后，由于 为了扩大Smad信号在体内肌发生中的作用，我们将 确定Smad 3功能改变对细胞分化的影响， 将成肌细胞注射到正常骨骼肌组织和肌纤维中 在损伤后的再生和肌肉营养不良小鼠模型中。我们的研究 关于Smads的生肌调节功能的研究将提供关于如何 TGF-β和肽类生长因子一般调节间充质细胞 分化

DESCRIPTION: (provided by applicant): The overall goal in this proposal is to establish physiologically relevant models about how TGF-Beta signaling through the Smad pathway regulates the terminal differentiation of skeletal muscle cells. The first part of the project aims to characterize the mechanism(s) through which TGF-Beta-activated Smads repress the function of MyoD family of myogenic bHLH transcription factors and inhibit muscle differentiation. Specifically, these experiments will extend our initial finding about a role for Smad3 in repression of muscle-specific transcription by determining the underlying mechanism(s), as well as the contribution of each potential mechanism to the antagonistic effect of TGF-beta during myogenesis. The second aim of this proposal is to evaluate the physical and functional interaction between Smads and MEF2 family of transcription factors, and elucidate the impact of such interaction on myogenic differentiation. Finally, since it is important to extend the role of Smad signaling in myogenesis in vivo, we will determine the consequence of altered Smad3 function to the differentiation of myoblast cells injected to normal skeletal muscle tissues and myofiber regeneration following injury and in muscle dystrophy mouse models. Our study on the myogenic regulatory function of Smads will provide new insights on how TGF-beta and peptide growth factors in general, regulate mesenchymal cell differentiation.