Determine how protein synthesis is regulated during cell growth and division

项目概要/摘要 细胞生长和分裂是组织稳态、再生和癌症的基本过程 发展因此，细胞生长调节的研究对于理解受损组织是重要的 再生和肿瘤发生。 细胞生长和细胞分裂是通过相互调节来协调的，这两个过程一起 决定了细胞的基本属性，细胞大小联系的分子机制 这些过程之间的联系在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，其有助于维持细胞大小稳态。RB稀释机制依赖于 对细胞周期依赖性RB蛋白合成的影响，但其调控机制尚不清楚。 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 目前还不清楚我发现蛋白质合成效率，细胞生长效率的主要决定因素， 在G1/S过渡期增加，在每个细胞周期阶段随着细胞变大而减少，表明 整体蛋白质合成速率被主动调节以促进细胞周期进展和细胞大小控制。 关键的是，RB1 mRNA和总mRNA浓度都不是细胞周期依赖性的，这意味着先前的研究表明， 未知的翻译机制。 在这里，在这个建议中，我的目标是通过确定分子水平来解决我们知识中的这些空白。 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。 对细胞周期进程中RB蛋白合成（Aim 1）的研究将进一步揭示RB蛋白合成的分子机制。 细胞生长如何触发细胞分裂的基础，以及细胞周期中整体蛋白质合成的研究 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 从蛋白质合成调节的角度来研究细胞分裂。然后，研究蛋白质合成 在细胞生长过程中受到调节（Aim3）探索了细胞大小如何反馈调节生长的机制 率因此，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。 上述目标的实现将加深我们对这些基本分子机制的理解 调节蛋白质合成和细胞生长速率，因此对细胞和发育具有广泛的影响。 生物学此外，这项工作将提高我们对组织再生缺陷的理解， 肿瘤发生在优秀的导师、合作者和顾问团队的帮助下，我将接受 在定量生物学和分子生物学的尖端技术，并获得技能，我的职业生涯 发展总之，拟议的科学和培训计划为独立的 研究生涯中了解细胞生长的生理和病理条件下的原则。

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.