Size regulation in animal cells.

细胞的大小和物理尺寸是其身份的直接明显标志。大小差异区分细胞类型、生理条件和病理。尽管如此，指定细胞特定大小的机制仍然未知。这项提案的长期目标是了解动物细胞的特定大小是如何指定和调节的。调节细胞生长的中心是蛋白复合物mTORC 1，其是帽依赖性翻译的全局调节剂。此外，已经确定了Wnt、TGFb和Hippo/Warts途径对细胞生长的影响。尽管积累了知识，但一个相关的问题仍然存在：一组共同的途径如何在不同的细胞类型中指定不同的大小？在早期的工作中，我们提供了证据，细胞大小的歧视过程连接细胞生长与细胞分裂周期。具体来说，我们发现在细胞周期的G1期后期，生长变得与细胞大小成反比-较大的细胞比较小的细胞积累较少的质量（Nature，2013）。这种G1特异性过程的净结果是细胞间大小变异性的降低。细胞在大小上变得更加相似，因此细胞大小变得更加精细。在后续未发表的研究中，我们发现了两个独立过程的证据，这些过程有效地降低了增殖群体中细胞大小的变异性。第一个是细胞大小检查点门控退出细胞周期的G1期。第二个，也许是更有趣的发现，是在细胞周期的两个不同时间，单个细胞生长的速度与它们的大小成反比-较大的细胞比较小的细胞增加它们的大小慢。最后，我们发现，细胞大小的生长速率调节，但不是G1出口是由mTORC 1调节，并被雷帕霉素抑制。本提案的具体目标是确定这两个独立的大小歧视过程的分子机制。我们的重点不是细胞扩大的机制，而是细胞扩大如何协调以产生明确和特定的细胞大小。我们的问题触及了细胞生物学中一个基本的未知：单个细胞如何感知和监控它们的大小？为了解决这些问题，我们采取跨学科的方法。我们使用类似于统计物理学中使用的数学技术来回答大规模显微镜分析的生物学问题。

A cell's size and physical dimensions are immediately apparent signatures of its identity. Size differences distinguish cell types, physiological conditions and pathologies. Despite this, the mechanisms that specify a cell's particular size remain unknown. The long term goal of this proposal is to understand how the particular size of animal cells is specified and regulated. Central to the regulation of cell growth is the protein complex mTORC1, a global regulator of cap dependent translation. Additionally, influence on cell growth has been established for Wnt, TGFb and the Hippo/Warts pathways. Despite the accumulated knowledge, a pertinent question remains: how do a common set of pathways specify different sizes in different cell types? In an earlier work we provided evidence for a cell-size discriminating process linking cell growth with the cell division cycle. Specifically, we showed that late in the G1 phase of cell cycle, growth becomes inversely dependent on cell size - larger cells accumulate less mass than smaller ones (Nature, 2013). The net result of this G1-specific process is a decrease in the cell-to-cell size variability. Cells become more similar in size, hence cell size becomes more finely specified. In follow-up, unpublished, investigations we identified evidence for two separate processes that effectively reduce cell size variability in proliferating populations. The first is a cell size checkpoint gating exit from the G1 phase of cell cycle. The second, and perhaps more interesting finding, is that on two separate times in cell cycle, the rate with which individual cells grow becomes inversely proportional to their size - larger cells increase their size slower than smaller cells. Last, we showed that the growth-rate regulation of cell size but not the G1-exit is regulated by mTORC1 and is inhibited by rapamycin. The specific goal of this proposal is to identify the molecular mechanism for these two separate size discriminatory processes. Our focus will center not on mechanisms of cellular enlargement but on how cellular enlargement is coordinated to result in a definite and specific cell size. Our question strikes at a fundamental unknown in cell biology: how do individual cells sense and monitor their size? To address these questions we take an interdisciplinary approach. We use mathematical techniques analogous to those used in statistical physics to answer biological questions from analysis of large-scale microscopy.