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、生理状况和病理。尽管如此，决定细胞大小的机制仍然未知。这项提议的长期目标是了解动物细胞的特定大小是如何被指定和调节的。调节细胞生长的核心是蛋白质复合物mTORC1，它是帽依赖翻译的全局调节剂。此外，Wnt、TGFb和Hippo/Warts通路对细胞生长的影响已被证实。尽管积累了知识，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，证明细胞大小区分过程将细胞生长与细胞分裂周期联系起来。具体来说，我们发现在细胞周期的G1期后期，生长与细胞大小成反比——较大的细胞比较小的细胞积累的质量更少（Nature, 2013）。这种g1特异性过程的最终结果是细胞间大小变异性的减少。细胞在大小上变得更加相似，因此细胞的大小变得更加精细。在后续未发表的调查中，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可变性。第一种是细胞大小检查点从细胞周期G1期退出。第二个可能更有趣的发现是，在细胞周期的两个不同时期，单个细胞的生长速度与它们的大小成反比——大细胞比小细胞长得慢。最后，我们发现细胞大小的生长速率调节由mTORC1调节，而不是g1出口，并被雷帕霉素抑制。本提案的具体目标是确定这两个单独的大小区分过程的分子机制。我们的重点将不是集中在细胞扩大的机制，而是如何协调细胞扩大，导致一个明确的和特定的细胞大小。我们的问题触及了细胞生物学中一个基本的未知问题：单个细胞是如何感知和监测它们的大小的？为了解决这些问题，我们采取了跨学科的方法。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中的生物学问题。

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 In follow-up, unpublished, investigations we identified evidence for two separate processes that effectively reduce cell size variability in proliferating populations.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.