Sox11 function in muscle stem cells

项目总结 我的职业目标是成为一名独立的研究员，研究转录调控的功能。 干细胞用于改善再生医学的治疗方法。在这个项目中，我将使用鼠标模型来 研究一种称为肌肉卫星细胞(MuSCs)的干细胞群体的调节。再生函数 控制细胞命运选择的基因调控网络(通常是转录因子)。 在自我更新、静止和/或分化之间。我们的实验室最近使用了单细胞RNA- 对肌肉再生过程中不同细胞群体的基因表达进行测序。这一化验结果导致 转录因子sox11作为MUSCs候选标志物及其潜在调控因子的鉴定 MUSC分化。研究表明，Sox11可能调节WNT/WNT相关基因的表达。 β-连环蛋白-信号通路，已被证明在发育过程中诱导肌肉发生并促进 成年骨髓间充质干细胞对损伤反应的分化。要了解遗传要求和发病机制 SOX11在MSC中，该提案将解决以下目标：(1)确定#年SOX11的必要性 骨骼肌发育和对损伤的反应。我们将使用条件性和诱导性小鼠模型 特别是在肌肉祖细胞和成年MUSC池中敲除Sox11。这些实验将允许 我们来评估我们的假设，即Sox11在体内对MSC的分化是必不可少的。(2)评估 Sox11在WNT信号转导中的作用，并确定WNT激活是否可以修复分化缺陷 SOX11-KO成肌细胞。这一目标将评估我们关于sox11调节wnt信号通路的假说。 确保成肌细胞分化的基因。而sox11的基本功能已经在其他 组织中，它在肌肉发生中的作用尚不清楚。这项研究提案有可能将sox11确定为新的 通过对WNT途径组分的转录调控来调节MUSC的功能。这项提议将 毫无疑问，它在基因调控领域提供了出色的培训，因为它与肌肉干细胞功能有关。

PROJECT SUMMARY My career goal is to be an independent investigator researching the function of transcriptional regulation of stem cells towards improving therapies for regenerative medicine. In this project, I will use mouse models to study the regulation of a stem cell population called muscle satellite cells (MuSCs). The regenerative function of MuSCs are controlled by gene regulatory networks (often transcriptional factors) that govern cell fate choice among self-renewal, quiescence and/or differentiation. Our lab has recently employed single-cell RNA- sequencing to profile gene expression of various cell populations during muscle regeneration. This assay led to the identification of the transcription factor Sox11 as a candidate marker for MuSCs and a potential regulator of MuSC differentiation. Studies suggest that Sox11 may regulate the expression of genes involved in the WNT/ β-catenin-signaling pathway, which has been shown to induce myogenesis during development and promote differentiation of adult MuSCs in response to injury. To understand the genetic requirement and mechanism of Sox11 in MuSCs, the proposal will address the following aims: (1) Determine the necessity for Sox11 in skeletal muscle development and in response to injury. We will use conditional and inducible mouse models to specifically knock-out Sox11 in muscle progenitors and in the adult MuSC pool. These experiments will allow us to evaluate our hypothesis that Sox11 is essential for the differentiation of MuSCs in vivo. (2) Assess the role Sox11 plays in WNT-signaling and determine if WNT activation can restore differentiation defects in Sox11-KO myoblasts. This aim will evaluate our hypothesis that Sox11 regulates WNT-signaling pathway genes to secure myoblast differentiation. While the essential function of Sox11 has been described in other tissues, its role in myogenesis is unknown. This research proposal has the potential to identify Sox11 as novel regulator of MuSC function via its transcriptional regulation of WNT-pathway components. This proposal will undoubtedly provide excellent training in the field of gene regulation as it pertains to muscle stem cell function.