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、免疫应答、神经元发育、趋化性（细胞对化学梯度的感知）和细胞分裂中至关重要。对模型系统D. discoideum涉及方向感测和极化的基本问题。我们已经发现，一些信号和细胞骨架蛋白，是重要的极性在趋化性也是至关重要的双极形状的变化，细胞分裂过程中经历的细胞。信号传导酶PI3K和肿瘤抑制因子PTEN在趋化性和细胞分裂过程中均被定位。了解它们的调控可能对研究人员试图确定为什么这两个基因在许多癌症中突变或丢失具有重要意义。我们也在积极尝试确定导致细胞迁移和细胞分裂过程中发生的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检测方法来监测一类称为G蛋白的蛋白质的状态。这些G蛋白是非常重要的信号传导器，与它们偶联的受体是制药公司药物的主要靶点。我们的目标是：1）对感知机制进行建模，用刺激输入挑战细胞，并测量它们的反应，以深入了解机制如何工作。2)研究细胞极性过程中重要信号蛋白的定位，并通过新的遗传筛选发现新的组分。3)了解G蛋白循环的基本特性。这些项目将为处于不同职业阶段的研究人员提供重要的培训机会。我目前有一个访问学者开发新的趋化性测定和一个研究生和博士后研究员工作的几个方面的研究。我也有一些有才华的本科生，他们正在研究这个项目的各个方面。我打算积极招募更多的研究生（今年我有3个轮换学生）和另一个博士后研究员。在我的实验室工作将有助于揭示复杂的信号机制，导致细胞结构的变化，在各种动态的细胞过程。 公共卫生：细胞在分裂和移动时呈现出极化形态。我们正在使用变形虫Dictyosteoba作为模型系统，以了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发生突变或丢失。

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.