Determine how protein synthesis is regulated during cell growth and division

确定细胞生长和分裂过程中蛋白质合成的调节方式

基本信息

批准号：
10506035
负责人：
Shuyuan Zhang
金额：
$ 10万
依托单位：
STANFORD UNIVERSITY
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：
2022-09-07 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10506035
关键词：
Abnormal Cell Address Affect B-Lymphocytes Back Biogenesis Biology Cell Count Cell Cycle Cell Cycle Progression Cell Cycle Stage Cell Maintenance Cell Proliferation Cell Size Cell division Cell physiology Cells Cellular biology Complex Cyclin-Dependent Kinases Cyclins Data Development Developmental Biology Disease Equilibrium Feedback Feeds Foundations G1/S Transition Growth Homeostasis Human Hyperplasia Hypertrophy Impairment Investigation Knowledge Laws Lead Link Liver Malignant Neoplasms Mammalian Cell Mass Spectrum Analysis Measures Mediating Mentors Messenger RNA Molecular Molecular Biology Natural regeneration Pathologic Phase Physiological Process Property Protein Biosynthesis Proteins Proteome RB1 gene RNA-Binding Proteins Regulation Research Retinoblastoma Protein Ribosomal Proteins Ribosomal RNA Ribosomes S phase Technology Testing Tissues Training Training Programs Transfer RNA Translational Regulation Translations Work career career development cell growth cell growth regulation healing in vivo Model inhibitor insight live cell imaging liver cell proliferation rate of change skills time use tissue regeneration tumorigenesis

项目摘要

Project Summary/Abstract Cell growth and division are the essential processes for tissue homeostasis, regeneration, and cancer development. Therefore, the study of cell growth regulation is important for understanding impaired tissue regeneration and tumorigenesis. Cell growth and cell division are coordinated via mutual regulation, and these two processes together determine a fundamental cellular property, the cell size. The molecular mechanisms underlying the linkages between these processes are largely unknown. Cell growth can trigger cell division by diluting the cell cycle inhibitor RB, which contributes to the maintenance of cell size homeostasis. The RB dilution mechanism relies on the cell cycle-dependent synthesis of RB protein, but the mechanism regulating RB synthesis is still unclear. On the other hand, cell cycle and cell size can feed back to regulate cell growth rate, of which the mechanisms are yet unknown. I found that the protein synthesis efficiency, a major determinant of cell growth efficiency, increases at the G1/S transition and decreases as cells grow larger within each cell cycle phase, suggesting that the global protein synthesis rate is actively regulated to facilitate cell cycle progression and cell size control . Crucially, both RB1 mRNA and total mRNA concentrations are not cell cycle-dependent, implying previously unknown translational mechanisms. Here, in this proposal, I aim to address these gaps in our knowledge by determining the molecular mechanisms regulating RB synthesis and global protein synthesis during cell cycle progression and cell growth. The investigation of RB protein synthesis during cell cycle progression (Aim1) will further reveal the molecular basis of how cell growth triggers cell division, and the study on global protein synthesis during cell cycle progression (Aim2) will help us understand how cell cycle regulates cell growth. These two aims link cell growth with cell division from the perspective of protein synthesis regulation. Then, the study on how protein synthesis is regulated during cell growth (Aim3) explores the mechanism of how cell size feeds back to regulate growth rate. Thus, the three aims together set up a foundation towards a deeper understanding of the principles governing cell growth and proliferation. The completion of above aims will deepen our understanding of the fundamental molecular mechanisms regulating protein synthesis and cell growth rate, and therefore have broad impacts on cell and developmental biology. Moreover, this work will enhance our understanding of tissue regeneration deficiencies and tumorigenesis. With the help of an outstanding team of mentors, collaborators, and consultants, I will train in the cutting-edge technologies in quantitative biology and molecular biology, and acquire skills for my career development. Together, the proposed scientific and training program form a strong foundation for an independent research career in understanding the principles of cell growth under physiological and pathological conditions.

项目概要/摘要细胞生长和分裂是组织稳态、再生和癌症的重要过程发展。因此，细胞生长调节的研究对于了解受损组织非常重要再生和肿瘤发生。细胞生长和细胞分裂通过相互调节来协调，这两个过程共同作用确定细胞的基本特性，即细胞大小。连接背后的分子机制这些过程之间的关系很大程度上是未知的。细胞生长可以通过稀释细胞周期来触发细胞分裂抑制剂 RB，有助于维持细胞大小稳态。 RB稀释机制依赖于 RB蛋白的细胞周期依赖性合成受到影响，但调节RB合成的机制仍不清楚。另一方面，细胞周期和细胞大小可以反馈调节细胞生长速率，其机制尚不得而知。我发现蛋白质合成效率是细胞生长效率的主要决定因素，在 G1/S 转变时增加，并随着细胞在每个细胞周期阶段内变大而减少，这表明整体蛋白质合成速率受到积极调节，以促进细胞周期进展和细胞大小控制。至关重要的是，RB1 mRNA 和总 mRNA 浓度均不依赖于细胞周期，这意味着之前未知的翻译机制。在这里，在这个提案中，我的目标是通过确定分子在细胞周期进程和细胞生长过程中调节RB合成和整体蛋白质合成的机制。细胞周期进程中 RB 蛋白合成的研究 (Aim1) 将进一步揭示分子细胞生长如何触发细胞分裂的基础，以及细胞周期期间整体蛋白质合成的研究进展（Aim2）将帮助我们了解细胞周期如何调节细胞生长。这两个目标将细胞生长联系起来从蛋白质合成调控的角度来看与细胞分裂有关。然后，研究蛋白质如何合成在细胞生长过程中受到调节 (Aim3) 探索细胞大小如何反馈调节生长的机制速度。因此，这三个目标共同为更深入地理解这些原则奠定了基础控制细胞生长和增殖。上述目标的完成将加深我们对基本分子机制的理解调节蛋白质合成和细胞生长速度，因此对细胞和发育有广泛的影响生物学。此外，这项工作将增强我们对组织再生缺陷和肿瘤发生。在由导师、合作者和顾问组成的优秀团队的帮助下，我将接受以下方面的培训：定量生物学和分子生物学的尖端技术，并获得适合我的职业的技能发展。总之，拟议的科学和培训计划为独立的研究生涯致力于理解生理和病理条件下细胞生长的原理。