The Role of TCTP in the Regulation of Skeletal Muscle Mass

描述(申请人提供)：哺乳动物的雷帕霉素靶标(MTOR)在调节骨骼肌质量中起着基础性的作用，然而，调控mTOR信号的分子机制(S)还只有模糊的定义。然而，目前正在取得进展，最近的研究表明，高度保守的翻译控制的肿瘤蛋白(TCTP)可以作为GTP酶Rheb的鸟嘌呤交换因子(Global)来调节mTOR信号转导。此外，以前的研究表明，促生长刺激可以通过对mTOR抑制剂雷帕霉素敏感的机制快速诱导TCTP的表达。基于这些观察，我们设想了一种机制，其中TCTP以前馈方式调节mTOR信号，这样的机制可以解释急性生长刺激(例如60次高抵抗收缩)如何促进mTOR信号的高度持续(&gt；36小时)激活。为了支持这种可能性，我们发现TCTP的表达通过mTOR依赖的机制在机械负荷时升高。此外，我们已经确定TCTP的过度表达足以诱导肥大。结合这些观察，我们得出了我们的中心假设：促生长刺激通过mTOR依赖的机制诱导TCTP表达，TCTP表达的变化反过来调节mTOR信号、蛋白质合成和纤维尺寸。为了验证这一假设，我们将结合体内生化、分子和遗传学方法，追求以下三个具体目标：1)确定各种促生长刺激是否通过mTOR依赖的机制诱导TCTP的表达；2)确定TCTP的表达是否调节蛋白质合成和纤维尺寸；以及3)确定TCTP是否通过mTOR依赖的机制诱导肥大，该机制要求TCTP对Rheb具有全球环境基金活性。这些研究的结果有望坚定地确立TCTP作为骨骼肌群的新型调节因子，并将为TCTP如何发挥这一作用提供洞察。此外，如果中心假设是正确的，结果将揭示一种机制，大大促进我们对mTOR信号和骨骼肌块是如何调节的理解。

DESCRIPTION (provided by applicant): The mammalian target of rapamycin (mTOR) plays a fundamental role in the regulation of skeletal muscle mass, however, the molecular mechanism(s) that regulate mTOR signaling have only been vaguely defined. Nevertheless, advances are being made, and recent studies suggest that the highly conserved translationally- controlled tumor protein (TCTP) can regulate mTOR signaling by acting as a guanine exchange factor (GEF) for the GTPase Rheb. Furthermore, previous studies have shown that the expression of TCTP can be rapidly induced by growth promoting stimuli through a mechanism that is sensitive to the mTOR inhibitor, rapamycin. Based on these observations, we have envisioned the potential for a mechanism in which TCTP regulates mTOR signaling in a feed-forward manner, and such a mechanism might explain how an acute growth stimulus (e.g. 60 high-resistance contractions) can promote a highly prolonged (>36hr) activation of mTOR signaling. In support of this possibility, we have found that TCTP expression is elevated in response to mechanical loading via an mTOR-dependent mechanism. Furthermore, we have determined that overexpression of TCTP is sufficient to induce hypertrophy. Combined, these observations have led us to our central hypothesis: growth promoting stimuli induce TCTP expression via an mTOR-dependent mechanism, and changes in TCTP expression, in-turn, regulate mTOR signaling, protein synthesis and fiber size. To test this hypothesis we will use a combination of in vivo biochemical, molecular and genetic approaches while pursuing the following three specific aims: 1) Determine if various growth promoting stimuli induce TCTP expression via an mTOR- dependent mechanism; 2) Determine if the expression of TCTP regulates protein synthesis and fiber size; and 3) Determine if TCTP induces hypertrophy through an mTOR-dependent mechanism that requires TCTP's GEF activity towards Rheb. The results of these studies are expected to firmly establish TCTP as novel regulator of skeletal muscle mass and they will provide insight into how TCTP exerts this effect. Furthermore, if the central hypothesis is correct, the outcomes will expose a mechanism that substantially advances our understanding of how mTOR signaling and skeletal muscle mass are regulated.