The role of mitochondrial regulation in cell lineage specification and function

摘要 线粒体调控在细胞谱系规范和功能中的作用 在细胞谱系指定期间，代谢重新编程以及转录和表观遗传 祖细胞的修饰是细胞适应细胞命运的不可或缺的部分，这是指导性线索。 当这一过程出错时，就会出现发育缺陷和恶性肿瘤。共同存在于所有 细胞系统，线粒体是代谢中心的生物能量、生物合成和信号传递细胞器。 改建。了解线粒体在谱系确定过程中的功能机制将对 在发病机制中细胞代谢和功能脱轨的治疗正常化。虽然线粒体 调控机制尚不清楚，我们已发表的初步工作揭示了线粒体的关键作用 细胞谱系确定过程中的代谢和线粒体动力学。此外，分化的细胞 在基础状态下继续接受低水平的结构性信号(“紧张性信号”)，这对细胞存活很重要 或功能。我们的研究表明，线粒体的调节在成熟期保持活跃。 紧张性信号下游的分化细胞，并揭示了这一过程的潜在新调节因子。这个 我们研究的主要主题是解开线粒体调节细胞的不同机制 血统分化和内环境平衡功能。在项目1中，我们将使用高分辨率成像来 描述活细胞中不同的线粒体形态和动态事件。使用基因工具，以及一个 器官培养系统来模拟细胞谱系规范，我们将破译线粒体动力学在 分化过程中的代谢重塑。在项目2中，使用一个复杂的系统将细胞转移到 在具有特定紧张性信号水平的环境中，我们将评估线粒体动力学和 在主音信号存在和不存在的情况下起作用。通过药物手段或基因 CRISPR/Ca9等修饰在分化细胞中的作用，我们将确定两者之间的因果关系 线粒体调节和维持细胞功能。在我们的工作完成后，我们将拥有 揭示了线粒体影响谱系规范和动态平衡的多种机制 功能。

ABSTRACT The role of mitochondrial regulation in cell lineage specification and function During cell lineage specification, metabolic reprogramming, together with transcriptional and epigenetic modifications in the progenitor cells are integral parts of cellular adaptations to the cell fate instructive cues. When this process goes awry, developmental defects as well as malignancies will occur. Common in all the cellular systems, mitochondria are bioenergetic, biosynthetic and signaling organelles central to metabolic remodeling. Understanding mechanisms of mitochondrial function during lineage specification will be critical for therapeutic normalization of derailed cellular metabolism and functions in pathogenesis. Though mitochondrial regulation is still unclear, our published and preliminary work revealed critical roles of mitochondrial metabolism and mitochondrial dynamics during cell lineage specification. Furthermore, differentiated cells continue to receive low-level, constitutive signaling in the basal state (“tonic signals”), important for cell survival or functions. Our research suggested that mitochondrial regulation is actively maintained in mature differentiated cells downstream of tonic signals and revealed potential new regulators for this process. The overarching theme of our research is to unravel the diverse mitochondria mediated mechanisms regulating cell lineage differentiation and homeostatic functions. In Project 1, we will use high resolution imaging to characterize distinct mitochondrial morphology, and dynamic events in live cells. Using genetic tools, and an organ culture system to model cell lineage specification, we will decipher the role of mitochondrial dynamics in metabolic remodeling during differentiation. In Project 2, using a sophisticated system of transferring cells into environments with defined levels of tonic signals, we will assess the alterations in mitochondrial dynamics and functions in the presence and absence of tonic signals. Through pharmacological means or genetic modifications such as CRISPR/Ca9 in differentiated cells, we will determine the causal relationship between mitochondrial regulation and maintenance of cellular functions. Upon completion of our work, we will have uncovered the versatile mechanisms by which mitochondria influence lineage specification and homeostatic functions.