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

• 批准号: 10798885
• 负责人: Meng Zhao
• 金额: $ 6.79万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/10798885
• 关键词: Bioenergetics; Biogenesis; Biology; Cell Differentiation process; Cell Lineage; Cell Survival; Cell model; Cell physiology; Cells; Clustered Regularly Interspaced Short Palindromic Repeats; Cues; Defect; Development; Disease; Environment; Epigenetic Process; Eukaryotic Cell; Event; Excision; Functional disorder; Genetic; Genetic Transcription; Maintenance; Malignant Neoplasms; Mediating; Metabolic; Metabolism; Mitochondria; Modification; Morphology; Organ Culture Techniques; Organelles; Pathogenesis; Physiology; Process; Publishing; Regulation; Research; Role; Signal Transduction; Specific qualifier value; System; Therapeutic; Work; high resolution imaging; mitochondrial metabolism; pharmacologic; public health relevance; stem cells; tool; trafficking

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.

摘要 线粒体调节在细胞谱系特化和功能中的作用 在细胞谱系特化过程中，代谢重编程，以及转录和表观遗传 祖细胞中的修饰是细胞适应细胞命运指示线索的组成部分。 当这个过程出错时，发育缺陷和恶性肿瘤都会发生。常见于所有 在细胞系统中，线粒体是生物能的、生物合成的和信号传导的细胞器，对代谢至关重要。 重塑理解线粒体功能在谱系特化过程中的机制对于 治疗正常化的脱轨细胞代谢和功能的发病机制。虽然线粒体 虽然调控机制尚不清楚，但我们已发表的和初步的工作揭示了线粒体的关键作用， 代谢和线粒体动力学过程中的细胞谱系规范。此外，分化的细胞 在基础状态下继续接收低水平的组成性信号（“紧张性信号”），这对细胞存活很重要 或功能。我们的研究表明，在成熟的细胞中， 分化的细胞下游的紧张信号，并揭示了潜在的新的监管机构，这一进程。的 我们研究的首要主题是揭示不同的线粒体介导的调节细胞凋亡的机制。 谱系分化和稳态功能。在项目1中，我们将使用高分辨率成像， 表征不同的线粒体形态和活细胞中的动态事件。使用基因工具， 器官培养系统来模拟细胞谱系特化，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 在具有确定水平的紧张信号的环境中，我们将评估线粒体动力学的改变， 在存在和不存在紧张性信号的情况下发挥作用。通过药理手段或遗传 在分化细胞中的CRISPR/Ca 9修饰，我们将确定 线粒体调节和维持细胞功能。我们的工作完成后， 揭示了线粒体影响谱系特化和体内平衡的多功能机制 功能协调发展的