Lipid Signaling in Chemotaxis

趋化作用中的脂质信号传导

基本信息

批准号：
8887423
负责人：
Miho Iijima
金额：
$ 31.75万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8887423
关键词：
Actins Address Amoeba genus Arthritis Asthma Atherosclerosis Back Behavior Binding Binding Proteins Biochemistry Biological Assay Cell membrane Cells Cellular biology Chemicals Chemotactic Factors Chemotaxis Complex Controlled Environment Cytoskeleton Cytosol Development Dictyostelium Disease Engineering Ensure Eukaryotic Cell Event Funding Genetic Goals Guanine Nucleotide Exchange Factors Guanosine Triphosphate Phosphohydrolases Human Hypersensitivity Immune response Inflammation Lead Link Lipids Malignant Neoplasms Mediating Membrane Microfilaments Modeling Molecular Morphogenesis Myosin ATPase Myosin Type I Neoplasm Metastasis Outcome PTEN gene Pathogenesis Pathologic Processes Pattern Phosphatidylinositols Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Physiological Physiological Processes Play Positioning Attribute Process Production Protein Microchips Proteomics Proto-Oncogene Proteins c-akt Race Recruitment Activity Regulation Research Research Project Grants Role Second Messenger Systems Signal Transduction Testing Tissues Translating Wound Healing angiogenesis axon guidance base cancer therapy cell motility extracellular fluorescence microscope genetic regulatory protein genome-wide high throughput screening human disease innovation insight knockout gene migration neuron development polymerization protein protein interaction public health relevance receptor rho GTP-Binding Proteins second messenger tool tripolyphosphate tumor

项目摘要

DESCRIPTION (provided by applicant): Directed cell migration toward chemoattractants, termed chemotaxis, is central to many physiologic events such as axon guidance, wound healing, and tissue morphogenesis. Inappropriate chemotaxis is a key feature of many human diseases, including tumor metastasis, asthma, arthritis, and atherosclerosis. Understanding the mechanisms of chemotaxis is therefore vital for understanding these chemotaxis-related diseases. The long- term goal of our research is to reveal how cells sense their chemical environment and control their migratory behaviors. Using Dictyostelium amoebae as our discovery tool and human cells as our translational tool, we focus on the potent intracellular signal phosphatidylinositol-3,4,5-triphosphate (PIP3), which is produced at the leading edge of cells and reorganizes the actin cytoskeleton. An important, but unanswered, question in the field of chemotaxis is how cells stably maintain the signaling network and remodel the actin cytoskeleton in chemoattractant gradients. To address this fundamental problem, our current studies identified: i) a signaling step that stabilizes directional sensing by persistently orientig Ras activation and PIP3 production, ii) a molecular link that directly binds to both PIP3 and the actin cytoskeleton, and iii) a conserved process in Dictyostelium and humans that turns off PIP3 signaling through translocation of the PIP3 phosphatase PTEN to the plasma membrane. In the next funding period, we propose to study each of these regulatory events and the mechanisms by which chemotactic signaling controls cell migration with high precision. In Aim 1, we will determine how directional sensing is spatially directed toward chemoattractants. We hypothesize that the activation of Ras GTPases and PIP3 production that occurs at the leading portion of cells is regulated by active Rho GTPases located at the rear end through chemical gradients. We will examine how Rho GTPases transmit signal to Ras GTPases. In Aim 2, we will determine how PIP3-binding monomeric myosin I converts the PIP3 signal to the actin cytoskeleton. We will test three models for the function of myosin I in cytoskeletal remodeling: connecting actin filaments to the plasma membrane, directly polymerizing actin, and recruiting actin nucleation factors. In Aim 3, we will delineate how human PTEN is recruited to the plasma membrane. We hypothesize that previously unidentified PTEN receptors in the plasma membrane mediate this process in human cells. We will examine the function of newly identified human PTEN-binding proteins in the localization of PTEN. Moreover, we will further determine the functional importance of the receptors in PIP3 signaling. The outcomes of our research are expected to provide a conceptual breakthrough into two central events in chemotaxis, directional sensing and cytoskeletal rearrangements, and may lead to development of chemotaxis-based treatments for cancer and inflammation.

描述（由申请人提供）：定向细胞向化学引诱物迁移，称为趋化性，是许多生理事件的核心，例如轴突引导、伤口愈合和组织形态发生，不适当的趋化性是许多人类疾病的关键特征，包括肿瘤转移、哮喘。因此，了解趋化性机制对于了解这些趋化性相关疾病至关重要。我们研究的长期目标是揭示细胞如何发生趋化性。使用阿米巴盘基网柄菌作为我们的发现工具和人类细胞作为我们的翻译工具，我们专注于有效的细胞内信号磷脂酰肌醇-3,4,5-三磷酸（PIP3），它是在趋化性领域中一个重要但尚未解答的问题是细胞如何稳定地维持信号网络和肌动蛋白细胞骨架。为了解决这一基本问题，我们目前的研究确定了：i) 通过持续定向 Ras 激活和 PIP3 产生来稳定定向传感的信号传导步骤，ii) 直接与 PIP3 和 PIP3 结合的分子链接。肌动蛋白细胞骨架，以及 iii) 盘基网柄菌和人类中的一个保守过程，通过将 PIP3 磷酸酶 PTEN 易位至在下一个资助期间，我们建议研究这些调控事件以及趋化信号以高精度控制细胞迁移的机制。在目标 1 中，我们将确定定向传感如何在空间上针对趋化剂。保留了发生在细胞前部的 Ras GTP 酶的激活和 PIP3 的产生是由位于后端的活性 Rho GTP 酶通过化学梯度调节的。我们将研究 Rho GTP 酶如何将信号传递给细胞。在目标 2 中，我们将确定 PIP3 结合单体肌球蛋白 I 如何将 PIP3 信号转换为肌动蛋白细胞骨架。我们将测试肌球蛋白 I 在细胞骨架重塑中的功能的三种模型：直接将肌动蛋白丝连接到质膜。聚合肌动蛋白和招募肌动蛋白成核因子在目标 3 中，我们将描述如何将人类 PTEN 招募到质膜上。质膜中未识别的 PTEN 受体介导人类细胞中的这一过程。我们的研究预计将为趋化、定向传感和细胞骨架重排的两个中心事件提供概念性突破，并可能导致基于趋化的癌症和炎症治疗的发展。