Sox11 function in muscle stem cells

项目摘要 我的职业目标是成为一名独立的研究人员，研究转录调控的功能， 干细胞对改善再生医学疗法的作用。在这个项目中，我将使用鼠标模型， 研究称为肌肉卫星细胞（MuSC）的干细胞群的调节。再生功能 的MuSC是由基因调控网络（通常是转录因子）控制的，这些基因调控网络控制着细胞的命运选择 自我更新、静止和/或分化。我们的实验室最近使用了单细胞RNA 测序以分析肌肉再生期间各种细胞群体的基因表达。该试验导致 将转录因子Sox 11鉴定为MuSC的候选标记物和MuSC的潜在调节因子， MuSC分化。研究表明，Sox 11可能调节WNT/ β-连环蛋白信号通路，已被证明在发育过程中诱导肌生成， 成年MuSC对损伤的反应。为了了解遗传要求和机制， Sox 11在MuSC中的应用，该提案将解决以下目标：（1）确定Sox 11在MuSC中的必要性。 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， 特异性敲除肌肉祖细胞和成体MuSC库中的Sox 11。这些实验将使 我们评估我们的假设，即Sox 11是必需的MuSCs在体内的分化。(2)评估 Sox 11在WNT信号传导中的作用，并确定WNT激活是否可以恢复分化缺陷。 Sox 11-KO成肌细胞。这一目的将评估我们的假设，Sox 11调节WNT信号通路 确保成肌细胞分化的基因。虽然Sox 11的基本功能已经在其他文献中描述， 组织，其在肌生成中的作用是未知的。这项研究提案有可能将Sox 11鉴定为新的 通过WNT途径组分的转录调节，调节MuSC功能。这项建议会 毫无疑问，在基因调控领域提供了极好的训练，因为它涉及肌肉干细胞功能。

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.