Regulation of Polarized Traffic by PI-Metabolizing Enzymes

PI 代谢酶对极化交通的调节

基本信息

批准号：
7257215
负责人：
Ora A Weisz
金额：
$ 30.5万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-07-15 至 2009-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7257215
关键词：
1-Phosphatidylinositol 3-Kinase 1-Phosphatidylinositol 4-Kinase ADP-Ribosylation Factors Abbreviations Actins Adenoviruses Apical Binding Biochemical Canis familiaris Cells Complex Data Defect Disease Dynamin Dynamin III Endoglycosidases Endoplasmic Reticulum Enzymes Epithelial Cells Equilibrium Event Generations Glutathione S-Transferase Glycosylphosphatidylinositols Golgi Apparatus Guanine Nucleotide Exchange Factors Individual Influenza Hemagglutinin Inositol Kidney Laboratories Lipids Localized MDCK cell Mediating Membrane Protein Traffic Metabolism Molecular Mutation Normal Statistical Distribution Oculocerebrorenal Syndrome Pathway interactions Phosphatidic Acid Phosphatidylinositol 4,5-Diphosphate Phosphatidylinositol Phosphates Phosphatidylinositols Phospholipase C Phospholipase D Phosphoric Monoester Hydrolases Phosphotransferases Polyphosphates Protein Isoforms Protein Overexpression Proteins Regulation Relative (related person)Role Site Structure Testing Transmembrane Transport Vesicle Vesicular stomatitis Indiana virus Wiskott-Aldrich Syndrome actin-related protein 3 apical membrane design inositol-1,4,5-trisphosphate 5-phosphatase interest kidney cell lipid metabolism myo-inositol-1 (or 4)-monophosphatase phosphatidylinositol 4-phosphate phosphatidylinositol phosphate platelet protein P47 research study streptolysin O trafficking trans-Golgi Network vesicular stomatitis virus G protein

项目摘要

DESCRIPTION (provided by applicant): The local generation of distinct phosphatidylinositol (PI) lipid species has been implicated in the regulation of numerous membrane trafficking events and in the control of cytoskeletal dynamics. The compartmentalized synthesis of noninterchangeable pools of PIs by PI-metabolizing enzymes is critical to the cell's ability to control these multiple PI-dependent functions independently. We are interested in the role of phosphatidylinositol kinases and inositol polyphosphate phosphatases in polarized membrane traffic in renal epithelial cells, and have found that apical and basolateral biosynthetic pathways are differentially sensitive to overexpression of the PI metabolizing enzymes PI-4 kinase beta and PI-5 kinase alpha. Moreover, the observation that Lowe Syndrome (a disease with severe renal manifestations) is caused by molecular defects in a Golgi-tocalized PI-catabolizing enzyme suggests a role for inositol polyphosphate 5-phosphatase activity in biosynthetic transport. In this proposal, we will correlate the effects of expressing individual PI-metabolizing enzymes on transport with actual changes in PI lipid composition across the Golgi complex and test hypotheses to explain the mechanisms by which distinct PI species regulate membrane traffic. These experiments will significantly enhance our understanding of how localized PI synthesis operates at a molecular level to regulate polarized biosynthetic traffic in normal and disease states.

描述（由申请人提供）：不同磷脂酰肌醇（PI）脂质种类的局部生成涉及许多膜运输事件的调节和细胞骨架动力学的控制。 PI 代谢酶对不可互换的 PI 库的分区合成对于细胞独立控制这些多种 PI 依赖性功能的能力至关重要。我们对磷脂酰肌醇激酶和肌醇多磷酸磷酸酶在肾上皮细胞极化膜运输中的作用感兴趣，并发现顶端和基底外侧生物合成途径对 PI 代谢酶 PI-4 激酶 β 和 PI-5 的过度表达具有不同的敏感性。激酶α。此外，Lowe 综合征（一种具有严重肾脏表现的疾病）是由高尔基体化 PI 分解代谢酶的分子缺陷引起的观察结果表明肌醇多磷酸 5-磷酸酶活性在生物合成转运中的作用。在本提案中，我们将表达单个 PI 代谢酶对运输的影响与高尔基复合体中 PI 脂质成分的实际变化相关联，并测试假设以解释不同 PI 物种调节膜运输的机制。这些实验将显着增强我们对局部 PI 合成如何在分子水平上调节正常和疾病状态下极化生物合成交通的理解。