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

 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）：定向细胞向趋化因子迁移，称为趋化性，是许多生理事件的核心，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感知其化学环境并控制其迁移行为。使用Dictyosteobacteriumamoeopathy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（PIP 3），这是在细胞的前沿产生的，并重组肌动蛋白细胞骨架。在趋化性领域中一个重要但尚未回答的问题是细胞如何稳定地维持信号网络并在趋化剂梯度中重塑肌动蛋白细胞骨架。为了解决这个根本问题，我们目前的研究确定了：i）通过持续定向Ras激活和PIP 3产生来稳定定向传感的信号传导步骤，ii）直接结合PIP 3和肌动蛋白细胞骨架的分子连接，以及iii）网骨藻和人类中的保守过程，其通过PIP 3磷酸酶PTEN易位到质膜来关闭PIP 3信号传导。在下一个资助期内，我们建议研究这些调控事件中的每一个，以及趋化信号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指向化学引诱物。我们推测，Ras GTPases和PIP 3生产的激活发生在细胞的前部是由位于后端的活性Rho GTPases通过化学梯度调节。我们将研究Rho GTP酶如何将信号传输到Ras GTP酶。在目标2中，我们将确定如何PIP 3结合单体肌球蛋白I转换PIP 3信号的肌动蛋白细胞骨架。我们将测试三种模型的肌球蛋白I在细胞骨架重塑的功能：连接肌动蛋白丝的质膜，直接聚合肌动蛋白，并招募肌动蛋白成核因子。在目标3中，我们将描述人PTEN是如何被募集到质膜的。我们推测，以前未鉴定的PTEN受体在质膜介导这一过程中的人类细胞。我们将研究新发现的人PTEN结合蛋白在PTEN定位中的功能。此外，我们将进一步确定PIP 3信号传导中受体的功能重要性。我们的研究成果有望为趋化性、定向传感和细胞骨架重排中的两个中心事件提供概念上的突破，并可能导致开发基于趋化性的癌症和炎症治疗方法。