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: 10404449
• 负责人: DANIEL J LEW
• 金额: $ 46.23万
• 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 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10404449
• 关键词: Address; Back; Cell Cycle; Cell Cycle Regulation; Cell Nucleus; Cell Polarity; Cell Shape; Cells; Cellular biology; Chemicals; Complex; Computer Models; Development; Disease; Environment; Eukaryotic Cell; Event; Feedback; Genetic Models; Goals; Grant; Instruction; Life Style; Malignant Neoplasms; Medical; Microscopy; Neoplasm Metastasis; Organelles; Partner in relationship; Pheromone; Regulation; Research; Shapes; Signal Transduction; Site; Specific qualifier value; System; Work; Yeast Model System; Yeasts; cell behavior; cell growth; cell motility; cell type; fungus; insight; interest; novel; 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 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