Lipid Signaling in Chemotaxis

趋化作用中的脂质信号传导

基本信息

批准号：
8536832
负责人：
Miho Iijima
金额：
$ 29.47万
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 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8536832
关键词：
1-Phosphatidylinositol 3-Kinase Actins Arthritis Asthma Atherosclerosis Binding Binding Proteins Biochemistry Biological Assay Biological Models Cell membrane Cells Cellular biology Chemicals Chemotactic Factors Chemotaxis Complex Cytoskeleton Defect Development Dictyostelium Dictyostelium discoideum Disease Eukaryotic Cell Event Experimental Models Genes Genetic Goals Guanine Nucleotide Exchange Factors Human body In Vitro Inflammation Lead Life Link Lipids Maintenance Malignant Neoplasms Mediating Molecular Morphogenesis Neoplasm Metastasis Outcome PH Domain PTEN gene Pathogenesis Pathway interactions Phosphatidylinositols Phospholipase A2 Phosphoric Monoester Hydrolases Phosphorylation Physiological Play Postdoctoral Fellow Process Production Protein Binding Proteins Proteomics Regulation Research Research Proposals Role Signal Pathway Signal Transduction Signaling Molecule Source Surface Tissues Translating Two-Hybrid System Techniques Work Wound Healing Yeasts axon guidance base cancer therapy cell motility cellular imaging extracellular genetic regulatory protein genome wide association study genome-wide human Huntingtin protein human disease in vivo insight member novel phosphoinositide-3,4,5-triphosphate polymerization professor public health relevance ran-binding protein 1 response rho GTP-Binding Proteins tripolyphosphate tumor

项目摘要

DESCRIPTION (provided by applicant): Chemotaxis, a process in which cells migrate toward higher concentrations of chemoattractants, is important for a variety of physiological events such as axon guidance, wound healing, and tissue morphogenesis. Inappropriate chemotaxis leads to many human diseases including tumor metastasis, asthma, arthritis and atherosclerosis. The long-term goal of our research is to reveal the molecular mechanism of chemotaxis and to understand the pathogenesis of chemotaxis- related human diseases. Using Dictyostelium discoideum as our experimental model system, we have demonstrated that phosphatidylinositol 3,4,5 triphosphate (PIP3) plays a critical role for intracellular signaling in chemotaxis. PIP3 is highly enriched at the leading edge of cells and activates downstream signaling events such as remodeling of the actin cytoskeleton. We have demonstrated that the intracellular level and localization of PIP3 are regulated by a lipid phosphatase, PTEN. PTEN is located at the rear end of chemotaxing cells and restricts the production of PIP3 at the leading edge. The local accumulation of PIP3 stimulates actin polymerization to extend pseudopods toward the source of chemoattractant. To date, it is unknown how the localization and activity of PTEN are regulated, and how PIP3 signaling is translated into reorganization of the actin cytoskeleton. In this research proposal, we will use a combination of genetics, biochemistry, cell biology and proteomics to achieve the following specific aims: 1) To determine how phosphorylation regulates the localization and activity of PTEN; 2) To define the functions of two proteins required for chemotaxis - Huntingtin and GxcT, a novel guanine nucleotide exchange factor for Rho GTPases; 3) To identify novel components that link PIP3 signaling and the actin cytoskeleton using proteomic approaches as well as genome-wide characterization of PH-domain containing proteins. The outcomes of our research are expected to provide novel insights into molecular mechanisms of chemotaxis and may lead to development of chemotaxis-based treatments for cancer and inflammation. PUBLIC HEALTH RELEVANCE: We study chemotaxis, a process in which cells sense extracellular chemical compounds and move toward the source of chemicals. Chemotaxis is highly relevant to development and maintenance of healthy human body as well as the pathogenesis of many diseases such as cancer, asthma, arthritis and atherosclerosis. The long-term goal of our study is to understand how chemotaxis works and how defects in chemotaxis cause human diseases using a variety of approaches including genetics, biochemistry, cell biology and proteomics.

描述（由申请人提供）：趋化性是细胞向更高浓度的趋化剂迁移的过程，对于多种生理事件（例如轴突引导、伤口愈合和组织形态发生）很重要。不适当的趋化性会导致许多人类疾病，包括肿瘤转移、哮喘、关节炎和动脉粥样硬化。我们研究的长期目标是揭示趋化性的分子机制，了解趋化性相关人类疾病的发病机制。使用盘基网柄菌作为我们的实验模型系统，我们证明了磷脂酰肌醇 3,4,5 三磷酸 (PIP3) 在细胞内信号传导中发挥着关键作用。 PIP3 在细胞前缘高度富集，并激活下游信号转导事件，例如肌动蛋白细胞骨架的重塑。我们已经证明 PIP3 的细胞内水平和定位受脂质磷酸酶 PTEN 调节。 PTEN 位于趋化细胞的后端，限制前缘 PIP3 的产生。 PIP3 的局部积累刺激肌动蛋白聚合，使伪足向化学引诱剂的来源延伸。迄今为止，尚不清楚 PTEN 的定位和活性是如何调节的，以及 PIP3 信号如何转化为肌动蛋白细胞骨架的重组。在本研究计划中，我们将结合遗传学、生物化学、细胞生物学和蛋白质组学来实现以下具体目标：1）确定磷酸化如何调节PTEN的定位和活性； 2) 定义趋化所需的两种蛋白质的功能——亨廷顿蛋白和GxcT，一种新型的Rho GTPases鸟嘌呤核苷酸交换因子； 3) 使用蛋白质组学方法以及含有 PH 结构域的蛋白质的全基因组表征来识别连接 PIP3 信号传导和肌动蛋白细胞骨架的新成分。我们的研究结果有望为趋化性的分子机制提供新的见解，并可能导致基于趋化性的癌症和炎症治疗的发展。公共健康相关性：我们研究趋化性，这是细胞感知细胞外化合物并向化学物质来源移动的过程。趋化性与健康人体的发育和维持以及癌症、哮喘、关节炎和动脉粥样硬化等许多疾病的发病机制密切相关。我们研究的长期目标是利用遗传学、生物化学、细胞生物学和蛋白质组学等多种方法了解趋化性如何发挥作用以及趋化性缺陷如何导致人类疾病。