Lipid Signaling in Chemotaxis

趋化作用中的脂质信号传导

• 批准号: 9100827
• 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
• 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/9100827
• 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; Health; 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; receptor; rho GTP-Binding Proteins; second messenger; tool; tripolyphosphate; tumor; 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; Health; 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; receptor; rho GTP-Binding Proteins; second messenger; tool; tripolyphosphate; tumor

 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（由适用提供）：定向细胞向趋化剂（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，关节炎和动脉粥样硬化。因此，了解趋化性的机制对于理解这些与趋化性有关的疾病至关重要。我们研究的长期目标是揭示细胞如何感知其化学环境并控制其迁移行为。使用Dictyostelium Amoebae作为我们的发现工具，将人类细胞作为我们的翻译工具，我们专注于潜在的细胞内信号磷脂酰肌醇-3,4,5-三磷酸（PIP3），该磷酸（PIP3）是在细胞前缘产生的，并重新组织了肌动蛋白细胞骨骼。在趋化性领域中，一个重要但尚未解决的问题是细胞如何稳定信号网络并重塑化学吸收剂梯度中的肌动蛋白细胞骨架。 To address this fundamental problem, our current studies identified: i) a signaling step that stabilizes directive sensitivity 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 photophatase PTEN to the plasma membrane.在下一个资金期间，我们建议研究这些调节事件中的每一个以及趋化信号传导以高精度控制细胞迁移的机制。在AIM 1中，我们将确定如何经常针对化学吸引剂。我们假设在细胞的主要部分发生的Ras GTPase和PIP3产生的激活受到后端的活性Rho GTPases通过化学梯度调节。我们将研究Rho GTPases如何将信号传输到RAS GTPases。在AIM 2中，我们将确定PIP3结合单体肌球蛋白I I如何将PIP3信号转换为肌动蛋白细胞骨架。我们将测试三个模型，以实现肌球蛋白I在细胞骨架重塑中的功能：将肌动蛋白丝与质膜连接，直接聚合肌动蛋白并募集肌动蛋白成核因子。在AIM 3中，我们将描述如何将人类PTEN招募到质膜。我们假设质膜中先前统一的PTEN受体介导了人类细胞中的这一过程。我们将研究新鉴定的人类PTEN结合蛋白在PTEN定位中的功能。此外，我们将进一步确定受体在PIP3信号传导中的功能重要性。我们的研究结果有望为趋化性，定向感应和细胞骨架重排的两个核心事件提供概念突破，并可能导致基于趋化性的癌症和炎症的疗法发展。