Les mécanismes liant la dynamique mitochondriale à l'état de quiescence et à l'activation des cellules souches musculaires

线粒体动力与静止与肌肉激活的机械主义

• 批准号: 577222-2022
• 负责人: Hulea, LauraL
• 金额: $ 3.28万
• 依托单位: Université de Montréal
• 依托单位国家: 加拿大
• 项目类别: Alliance Grants
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=760646
• 关键词: Les; canismes; liant; la; dynamique

Adult stem cells are necessary for normal tissue physiology and under conditions of stress, such as injury or advanced aging. Regulation of their state of dormancy (or quiescence) is important towards how adult stem cells are maintained, activated, as well as their regeneration potential. Yet, how this regulation takes places and the underlying cellular mechanisms are not fully understood.Our preliminary work has uncovered that physiological and transient changes in the shape of mitochondria, one of the major cellular organelles, regulate the quiescent state of adult muscle stem cells (MuSC). We observed that mitochondria in stem cells rapidly fragment in response to an environmental activation stimulus. This pushes the cells toward an exit from deep quiescence and is dependent on a major cellular complex called mTOR. Moreover, we have found that, following exit from dormancy, adult MuSC undergo modifications in histone protein complexes (epigenetic changes), which lead to changes in the way genes are expressed in the cells. This in turn could lead to physiological changes at the cellular and tissue level.In this proposal, we aim to investigate in depth(1) the role of mTOR complexes and the cellular processes they control in the exit from deep quiescence of adult MuSC.(2) what epigenetic changes occur following mitochondria fragmentation and the exit from dormancy of adult MuSC, and what is the causal role between these changes and the subsequence stem cell activation.To tackle these questions, we have formed a collaborative team of three laboratories, each with unique and complementary expertise: Dr Laura Hulea (mTOR complexes and the cellular processes they control), Dr Mireille Khacho (stem cells biology and mitochondria dynamics) and Dr Frédérick Mallette (epigenetic regulation and aging). Each laboratory has the know-how and the specific tools, both in tissue culture and using mice, to address the aforementioned interrogations.

成年干细胞对于正常组织生理和在压力的条件（例如损伤或晚期衰老）的条件下是必需的。对其休眠状态（或静止）的调节对于如何维持，激活以及其再生潜力对成年干细胞的方式很重要。然而，这种调节的发生方式和潜在的细胞机制尚未完全理解。我们的初步工作发现，主要的细胞细胞器之一是生理和瞬态的变化，它是成年肌肉干细胞（MUSC）的静止状态。我们观察到干细胞中的线粒体响应环境激活刺激而迅速碎片。这将细胞推向深度静止的出口，并取决于称为MTOR的主要细胞复合物。此外，我们发现，在退出休眠后，成年MUSC在组蛋白蛋白复合物（表观遗传变化）中经历了改变，这导致了基因在细胞中表达的方式的变化。反过来，这可能会导致细胞和组织水平的身体变化。在这一提议中，我们旨在在深度（1）MTOR复合物的作用以及它们在成年MUSC深度静止中控制的细胞过程。（2）表观遗传变化在线粒体碎片和衰减中发生的事物和临时的作用以及这些作用以及这些造成的作用以及这些作用之间发生的变化以及这些作用。这些问题，我们组成了一个由三个实验室组成的协作团队，每个团队都具有独特而互补的专业知识：Laura Hulea博士（MTOR Complextes和他们控制的细胞过程），Mireille Khacho博士（干细胞生物学和线粒体动力学）和FrédérickMaltette博士（frédérickMartette）（Epigentecentic and and egeenetic Condulation）。每个实验室在组织培养和使用小鼠中都有专有技术和特定工具来解决近似询问。