The role of mitochondrial regulation in cell lineage specification and function

线粒体调节在细胞谱系规范和功能中的作用

基本信息

批准号：
10818978
负责人：
Meng Zhao
金额：
$ 6.44万
依托单位：
OKLAHOMA MEDICAL RESEARCH FOUNDATION
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2027-06-30
项目状态：
未结题

项目摘要

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.

抽象的线粒体调节在细胞谱系规范和功能中的作用在细胞谱系规范、代谢重编程以及转录和表观遗传过程中祖细胞的修饰是细胞适应细胞命运指示线索的重要组成部分。当这个过程出现问题时，就会出现发育缺陷和恶性肿瘤。细胞系统中，线粒体是生物能量、生物合成和代谢中心的信号细胞器了解谱系规范过程中线粒体功能的机制对于通过线粒体使治疗性细胞代谢和功能脱轨正常化。调控仍不清楚，我们发表的和初步的工作揭示了线粒体的关键作用细胞谱系规范期间的代谢和线粒体动力学此外，分化的细胞。继续接收基础状态下的低水平组成性信号（“强直信号”），这对细胞生存很重要我们的研究表明线粒体调节在成熟过程中得到积极维持。分化了强直信号下游的细胞，并揭示了该过程的潜在新调节因子。我们研究的首要主题是揭示调节细胞的多种线粒体介导机制在项目 1 中，我们将使用高分辨率成像来进行谱系分化和稳态功能。使用遗传工具和活细胞中的不同线粒体形态和动态事件的特征。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的作用在项目 2 中，使用复杂的系统将细胞转移到分化过程中。在具有明确的强直信号水平的环境中，我们将评估线粒体动力学的变化和通过药理学手段或遗传手段在存在或不存在滋补信号的情况下发挥作用。分化细胞中的 CRISPR/Ca9 等修饰，我们将确定之间的因果关系线粒体调节和细胞功能的维持完成我们的工作后，我们将有。揭示了线粒体影响谱系规范和稳态的多种机制功能。