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

• 批准号: 10782629
• 负责人: DANIEL J LEW
• 金额: $ 23.19万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/10782629
• 关键词: Studies; cell; polarity; chemotropism; cycle

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.

抽象的 我们的研究重点是与细胞极性有关的基本问题。细胞极性描述了能力 细胞沿特定轴的空间组织其内部宪法。这对于细胞迁移至关重要 （细胞需要生成前部和背部的地方），也用于开发专门的细胞形状 许多细胞起作用需要。此外，极性机械的演变可以有助于 例如，几种疾病通过启用癌症转移。那是对机制的理解 调节和细胞极性的后果既具有基本利益和医学利益。 细胞极性的研究已经确定了以进化上的古老和构成为中心的核心机械 极性的主要调节剂称为CDC42。但是，仍然存在许多最有趣的问题 未解决。大多数单元仅在Cdc42中富含单个“ front”，但是有些单元格有更多的单元格 复杂形状可以指定几个站点以充当前线？细胞如何读取他们的环境 确定应定向极性轴的方向？一旦建立了极性， 精确的下游事件集精心策划以使每种单元格的形状正确？然后，如何 细胞知道它们是什么形状？ 我们使用独特的酵母模型系统来调查这些问题，并使用一个组合 尖端显微镜，遗传学和计算建模。我们以前的工作确定了积极的 反馈机制，解释了CDC42如何集中在极性位点以建立​​极性 轴。我们最近在酵母交配过程中进行极化的工作，当酵母细胞响应空间时 信息素的梯度提出了一种新的范式，称为探索性极化，用于跟踪化学 梯度。关于海洋真菌的新发现揭示了新颖的生活方式，其细胞生物学尚未是 特征。在接下来的5年赠款周期中，我们的主要目标是（i）解决细胞极性的方式 受细胞周期和信息素信号的调节； （ii）解决有关新的剩余的公开问题 探索性极化机制，使交配细胞能够彼此找到，并且（iii）了解如何 在每个细胞周期中制造几个芽的海洋真菌可以将其核和细胞器分开 不同的芽。我们被毒死以在上面提出的问题上取得重大进展，并利用 这些问题的答案，以提供远远超出酵母系统的见解。