Studies of 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: 10197950
• 负责人: DANIEL J LEW
• 金额: $ 67.42万
• 依托单位: DUKE UNIVERSITY
• 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 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10197950
• 关键词: Address; Back; Cell Cycle Checkpoint; Cell Cycle Regulation; Cell Polarity; Cell Shape; Cell model; Cell physiology; Cells; Chemicals; Complex; Computer Models; Cues; Disease; Environment; Eukaryotic Cell; Event; Feedback; Genetic Models; Growth; Link; Malignant Neoplasms; Medical; Microscopy; Neoplasm Metastasis; Partner in relationship; Pheromone; Regulation; Research; Shapes; Signaling Molecule; Site; Specific qualifier value; System; Work; Yeast Model System; Yeasts; base; cancer therapy; cell growth; cell motility; cell type; extracellular; insight; interest; migration; response

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 “master 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 for tracking chemical gradients. And our work on a yeast cell-cycle checkpoint responsive to cell shape now suggests a model for how cells know what shape they are. Based on these findings, 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， 称为Cdc42的极性“主调节器”。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Cdc42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Cdc42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 信息素梯度，提出了一种追踪化学梯度的新范式。我们的工作是 酵母细胞周期检查点对细胞形状的反应现在提出了细胞如何知道什么形状的模型 他们来了基于这些发现，我们准备在所提出的问题上取得重大进展 以上，并利用这些问题的答案，提供远远超出酵母的见解 系统