PI(3,4,5)P3 Regulates Cell Polarity During Chemotaxis and Cytokinesis

描述(由申请人提供)：细胞极化在形态发生、免疫反应、神经元发育、趋化性(细胞对化学梯度的感觉)和细胞分裂中是必不可少的。所提出的关于盘状藻模型系统的研究涉及定向传感和极化的基本问题。我们发现，在趋化过程中对极性很重要的一些信号和细胞骨架蛋白，也对细胞在细胞分裂过程中经历的双极形状变化至关重要。信号酶PI3K和抑癌基因PTEN在趋化和细胞分裂过程中相互定位。了解它们的调控可能对试图确定这两个基因在许多癌症中发生突变或丢失的原因的研究人员具有重要意义。我们还在积极尝试确定在细胞迁移和细胞分裂过程中导致其他信号和细胞骨架蛋白重新分布的分子步骤。最后，我们开发了一种强大的荧光分析方法来监测一类名为G蛋白的蛋白质的状态。这些G蛋白是极其重要的信号转导蛋白，与其偶联的受体是制药公司药物的主要靶点。我们的目标是：1)建立感知机制的模型，用刺激输入挑战细胞，并测量它们的反应，以深入了解该机制是如何工作的。2)研究细胞极性过程中重要信号蛋白的定位，发现具有新的遗传筛选的新成分。3)了解G蛋白循环的基本特性。这些项目将为处于职业生涯不同阶段的研究人员提供重要的培训机会。目前，我有一名访问学者正在开发新的趋化分析方法，一名研究生和一名博士后研究员正在研究这项研究的几个方面。我也有一些有才华的本科生，他们正在为这个项目的各个方面工作。我打算积极招收更多的研究生(我今年已经有3个轮班学生)和另一个博士后研究员。我实验室的工作将有助于揭示在各种动态细胞过程中导致细胞结构变化的复杂信号机制。 公共卫生：当细胞分裂和移动时，它们呈现两极分化的形态。我们正在使用Dictyostelials作为模型系统来理解控制这些细胞形状变化的基本机制。我们正在研究的许多同源成分在许多人类疾病中都发生了突变或丢失。

DESCRIPTION (provided by applicant): Cellular polarization is essential in morphogenesis, the immune response, neuronal development, chemotaxis (the sensing of chemical gradients by cells) and cell division. The proposed studies on the model system D. discoideum relate to the basic problems of directional sensing and polarization. We have found that a number of signaling and cytoskeletal proteins that are important for polarity during chemotaxis are also critical for the bipolar shape changes that a cell undergoes during cell division. The signaling enzymes PI3K and the tumor suppressor PTEN are reciprocally localized during both chemotaxis and cell division. Understanding their regulation may have important implications for investigators trying to determine why these two genes are mutated or lost in many cancers. We are also actively trying to determine the molecular steps that lead to the redistribution of other signaling and cytoskeletal proteins that occur during cell migration and cell division. Lastly, we have developed a powerful fluorescence assay to monitor the state of a class of proteins called G proteins. These G proteins are extremely important signal transducers and the receptors that couple to them are major targets for drugs by pharmaceutical companies. Our goals are to: 1) Model the sensing mechanism, challenge cells with stimulus inputs and measure their responses to gain insight into how the mechanism works. 2) Investigate the localization of important signaling proteins during cell polarity and find new components with novel genetic screens. 3) Understand the fundamental properties of the G protein cycle. These projects will provide significant training opportunities for researchers at various stages of their career. I currently have a visiting scholar developing new assays for chemotaxis and a graduate student and a postdoctoral fellow work on several aspects of the research. I also have a number of talented undergraduates who are working on various aspects of the project. I intend on actively recruiting more graduates students (I have had 3 rotations students this year) and another postdoctoral fellow. Work in my lab will help uncover the intricate signaling mechanisms that lead to changes in the cells architecture in a variety of dynamic cellular processes. PUBLIC HEALTH REVELANCE: Cells take on a polarized morphology when they divide and move. We are using the amoeba Dictyostelium as a model system to understand the basic mechanisms that control these changes in cell shape. Many of the homologous components we are studying are mutated or lost in many human diseases.