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Studies on cell polarity, chemotropism, and cell cycle control

细胞极性、趋化性和细胞周期控制的研究

基本信息

批准号：
10650791
负责人：
DANIEL J LEW
金额：
$ 70.6万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2027-06-30
项目状态：
未结题

项目摘要

ABSTRACT Our research is focused on fundamental questions related to cell polarity. Cell polarity describes the ability of cells to spatially organize their internal constituents along a specific axis. It is critical for cell migration (where cells need to generate a front and a back), and also for developing specialized cell shapes that are needed for many cells to function. In addition, derangements of the polarity machinery can contribute to several diseases, for example by enabling cancer metastases. Thus, an understanding of the mechanisms, regulation, and consequences of cell polarity is of both fundamental and medical interest. Studies on cell polarity have identified an evolutionarily ancient and conserved core machinery centered on a primary regulator of polarity called Cdc42. However, many of the most interesting questions remain unsolved. How is it that most cells only make a single “front” enriched in Cdc42, but some cells with more complex shapes can specify several sites to act as fronts? How do cells read their environment to determine the direction in which they should orient the polarity axis? Once polarity is established, how is the precise downstream set of events orchestrated to give each cell type the right shape? And then, how do cells know what shape they are? We use the uniquely tractable yeast model system to investigate these questions, and apply a combination of cutting-edge microscopy, genetics, and computational modeling. Our previous work identified a positive feedback mechanism that explains how Cdc42 becomes concentrated at polarity sites to establish a polarity axis. Our recent work on polarization during yeast mating, when yeast cells orient in response to spatial gradients of pheromones, suggests a new paradigm, called Exploratory Polarization, for tracking chemical gradients. And new findings on marine fungi reveal novel lifestyles whose cell biology has yet to be characterized. For the next 5-year grant cycle, our major goals are to (i) address how cell polarity is regulated by cell cycle and pheromone signaling; (ii) address remaining open questions about the new exploratory polarization mechanism that enables mating cells to find each other, and (iii) to understand how marine fungi that make several buds in each cell cycle can partition their nuclei and organelles among the different buds. We are poised to make significant advances on the questions posed above, and to exploit the answers to those questions to provide insights that extend well beyond the yeast system.

摘要我们的研究集中在与细胞极性相关的基本问题上。细胞极性描述了在空间上沿着特定的轴沿着组织它们的内部成分。它对细胞迁移至关重要（其中细胞需要产生正面和背面），并且还用于开发专门的细胞形状，需要许多细胞来运作。此外，极性机制的紊乱可能有助于几种疾病，例如通过使癌症转移。因此，对机制的理解，细胞极性的调节和后果是基本的和医学上感兴趣的。对细胞极性的研究已经确定了一个进化上古老而保守的核心机制，一个叫做Cdc 42的主要极性调节器然而，许多最有趣的问题仍然存在未破案件为什么大多数细胞只形成一个富含Cdc 42的“前线”，而有些细胞却有更多的“前线”呢？复杂的形状可以指定几个网站作为前线？细胞如何解读环境，决定他们应该将极性轴定向的方向？一旦极性建立，一系列精确的下游事件，精心安排，使每种细胞类型具有正确的形状？然后，细胞知道自己是什么形状吗我们使用独特的易处理的酵母模型系统来研究这些问题，并应用一个组合尖端的显微镜、遗传学和计算机建模。我们之前的研究发现了一种积极的反馈机制，解释了Cdc 42如何集中在极性位点以建立极性轴线我们最近的工作极化在酵母交配，当酵母细胞定向响应空间梯度的信息素，提出了一种新的范式，称为探索极化，用于跟踪化学梯度。关于海洋真菌的新发现揭示了新的生活方式，其细胞生物学尚未被表征了在下一个5年资助周期，我们的主要目标是（i）解决细胞极性是如何受细胞周期和信息素信号调节;（ii）解决有关新的探索极化机制，使交配细胞找到对方，（iii）了解如何海洋真菌在每个细胞周期中产生几个芽，可以将它们的细胞核和细胞器分配到细胞中。不同的花蕾我们准备在上述问题上取得重大进展，并利用这些问题的答案提供了远远超出酵母系统的见解。