Regulation of Polarized Traffic by PI-Metabolizing Enzymes

PI 代谢酶对极化交通的调节

• 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
• 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

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（由申请方提供）：不同磷脂酰肌醇（PI）脂质物质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PI不可互换池的区室化合成对于细胞独立控制这些多个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，并发现顶端和基底侧生物合成途径对PI代谢酶PI-4激酶β和PI-5激酶α的过度表达具有不同的敏感性。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分解代谢酶中的分子缺陷引起的，这一观察表明肌醇多磷酸5-磷酸酶活性在生物合成运输中的作用。在这项建议中，我们将相关的影响，表达个别PI代谢酶的运输与实际变化PI脂质组成的高尔基复合体和测试的假设，以解释不同的PI物种调节膜交通的机制。这些实验将显著增强我们对局部PI合成如何在分子水平上调节正常和疾病状态下的极化生物合成交通的理解。