Class III phosphoinositide 3-kinase Vps34 in autophagy and endocytosis

III 类磷酸肌醇 3-激酶 Vps34 在自噬和内吞作用中的作用

• 批准号: 8753927
• 负责人: Nadia Jaber
• 金额: $ 3.09万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8753927
• 关键词: 1-Phosphatidylinositol 3-Kinase; 3-methyladenine; Address; Afferent Neurons; Autophagocytosis; Autophagosome; Cell Lineage; Cell Survival; Cell membrane; Cell physiology; Cells; Clinical Trials; Complex; DNA Damage; Defect; Destinations; Development; Disease; Doctor of Philosophy; Early Endosome; Embryo; Endocytosis; Endosomes; Event; Fibroblasts; Genetic; Goals; Growth; Heart; Homeostasis; Housekeeping; Human; Hypoxia; Integral Membrane Protein; Intracellular Membranes; Investigation; Knock-out; Knockout Mice; Laboratories; Libraries; Lipids; Literature; Liver; Lysosomes; Maintenance; Malignant Neoplasms; Mammals; Membrane Protein Traffic; Molecular; Mus; Nutrient; Organelles; Pathway interactions; Phosphatidylinositide 3-Kinase Inhibitor; Phosphatidylinositols; Phospholipids; Phosphotransferases; Physiological; Play; Process; Proteins; Regulation; Reporting; Research; Role; Signaling Molecule; Sirolimus; Small Interfering RNA; Sorting - Cell Movement; Staging; Stress; Structure; Testing; Therapeutic; Tissues; Transferrin Receptor; Yeasts; anti-cancer therapeutic; base; design; extracellular; inhibition of autophagy; inhibitor/antagonist; inorganic phosphate; kinase inhibitor; late endosome; novel; phosphatidylinositol 3-phosphate; protein misfolding; public health relevance; receptor recycling; response; therapeutic target; therapy resistant; trafficking; wortmannin; yeast genetics

DESCRIPTION (provided by applicant): Vps34 is a lipid kinase that regulates membrane trafficking pathways like endocytosis and autophagy by generating phosphoinositol 3-phosphate, a lipid signaling molecule. Endocytosis is the process by which cells take up extracellular materials and transmembrane proteins, and sort them to their proper destinations. Endocytosis is necessary for cells to acquire nutrients and for appropriate growth control. Autophagy is an evolutionarily conserved process that promotes cell survival by serving a housekeeping role, and by providing extra nutrients when the cell is under stress. As both endocytosis and autophagy are important cellular events in cancer development and resistance to therapy, they have become targets for designing novel cancer therapeutics. Therefore, it is important to understand how these cellular events are regulated. Although Vps34 is implicated in both endocytosis and autophagy, determining its precise role has been hampered by the lack of specific inhibitors. Using a genetic knockout strategy we recently reported that Vps34 has a major role in autophagosome formation and the late stages of endocytosis, but may be dispensable at the early endosome. This proposal is designed to determine 1) the precise role of Vps34 during endocytosis by examining the functions of the early endosome, the process of endosome maturation and the functions of the late endosome in Vps34-deficient cells, and 2) how autophagy is regulated via Vps34 dependent or independent mechanisms. These studies will help provide a clearer picture of the exact roles of Vps34 in endocytosis and autophagy. This information will be critical for understanding the multifaceted functions of Vps34 and for the design of anti-cancer therapeutics targeting endocytosis or autophagy.

描述（由申请人提供）：Vps34是一种脂质激酶，通过产生磷酸肌醇3-磷酸（一种脂质信号分子）来调节膜运输途径，例如内吞作用和自噬。内吞作用是细胞吸收细胞外物质和跨膜蛋白并将它们分类到适当目的地的过程。内吞作用对于细胞获取营养和适当的生长控制是必要的。自噬是一种进化上保守的过程，它通过发挥管家作用并在细胞处于压力下时提供额外的营养来促进细胞存活。由于内吞作用和自噬都是癌症发展和治疗耐药中重要的细胞事件，因此它们已成为设计新型癌症疗法的目标。因此，了解这些细胞事件是如何调节的非常重要。尽管 Vps34 与内吞作用和自噬有关，但由于缺乏特异性抑制剂，确定其精确作用受到阻碍。我们最近利用基因敲除策略报道，Vps34 在自噬体形成和内吞作用的后期阶段发挥着重要作用，但在早期内体中可能是可有可无的。该提案旨在：1）通过检查 Vps34 缺陷细胞中早期内体的功能、内体成熟过程和晚期内体的功能，确定 Vps34 在内吞作用过程中的精确作用；2）如何通过 Vps34 依赖或独立机制调节自噬。这些研究将有助于更清楚地了解 Vps34 在内吞作用和自噬中的确切作用。此信息对于理解 Vps34 的多方面功能以及 针对内吞作用或自噬的抗癌疗法的设计。