Investigating the regulation of PI(3,4)P2 in migrating cells

研究迁移细胞中 PI(3,4)P2 的调节

• 批准号: 10291836
• 负责人: Marc Edwards
• 金额: $ 41.16万
• 依托单位: AMHERST COLLEGE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10291836
• 关键词: 1-Phosphatidylinositol 3-Kinase; Anabolism; Behavior; Biochemical; Biological Assay; Biosensor; Cell model; Cell physiology; Cells; Cues; Development; Dictyostelium; Disease; Environment; Enzyme-Linked Immunosorbent Assay; Enzymes; Family member; Feedback; Functional disorder; Goals; Human; Intervention; Knock-out; Knowledge; Liquid substance; Malignant Neoplasms; Mediating; Mediator of activation protein; Medical; Membrane; Mission; Modeling; Molecular; Monomeric GTP-Binding Proteins; Neoplasm Metastasis; Nerve Degeneration; Organism; Outcome; Pathology; Pharmacology; Phosphatidylinositol Phosphates; Phosphatidylinositols; Phosphotransferases; Play; Positioning Attribute; Regulation; Research; Role; Science; Signal Pathway; Signal Transduction; Structure; Testing; United States National Institutes of Health; Work; cell behavior; cell motility; college; developmental disease; inhibitor/antagonist; insight; live cell microscopy; loss of function; migration; mutant; neurodevelopment; particle; phosphatidylinositol 3,4-diphosphate; phosphoinositide-3,4-bisphosphate; recruit; spatiotemporal; tool; trafficking; tripolyphosphate; undergraduate student; uptake

Project Summary/Abstract This proposal seeks to elucidate the mechanism of PI(3,4)P2's role in migration. Phosphatidylinositols serve as critical mediators of cellular signaling. PI(3,4)P2 has emerged as a critical regulator of cell migration. It has recently been proposed that a mutually inhibitory feedback loop between Ras and PI(3,4)P2 regulates the dynamic extension and retraction of cellular protrusions. This proposal will elucidate the mechanism by which Ras regulates PI(3,4)P2 and establish PI(3,4)P2 as a bona fide regulator of Ras-dependent leading-edge dynamics. We will also provide insight into the regulation of PI(3,4)P2 in migrating cells by investigating the hypothesis that class PI- 3kinase PIKF regulates the biosynthesis of PI(3,4)P2 in Dictyostelium. Our work will also demonstrate that PIKF's role in migration is attributable to its ability to synthesize PI(3,4)P2. This work will provide significant insight into the feedback loops that regulate Ras-dependent activity. The molecular tools generated by this work will be instrumental in the pursuit of our long-term goals of elucidating the structure of the signaling networks that control migration. Phosphoinositide signaling plays an integral role in cellular signaling and the pathophysiology of numerous diseases. Therefore, this work is immediately relevant to our understanding of disease and the mission of the National Institutes of Health. Our proposed studies will provide undergraduate students with the opportunity to engage in rigorous and impactful science and will bolster the already robust research environment at Amherst College.

项目摘要/摘要 本研究旨在阐明Pi(3，4)P2‘S在细胞迁移中的作用机制。 磷脂酰肌醇是细胞信号转导的关键介质。PI(3，4)P2有 成为细胞迁移的关键调节因子。最近有人提议，一个 RAS和PI(3，4)P2之间的相互抑制反馈环调节动态 细胞突起的伸展和回缩。这项建议将澄清 RAS调节PI(3，4)P2并确立PI(3，4)P2为善意的机制 RAS相关前沿动态的调节器。我们还将深入了解 PI(3，4)P2在迁移细胞中的调节作用 3Kinase PIKF调节网柄基盘基团中PI(3，4)P2的生物合成。我们的工作将 也证明了PIKF在迁移中的作用归因于它合成 PI(3，4)P2.这项工作将提供对反馈循环的重要洞察力 调节RAS依赖的活动。这项工作产生的分子工具将是 有助于实现我们的长期目标，即阐明 控制迁移的信令网络。磷脂酰肌醇信号转导起着不可或缺的作用 在细胞信号和多种疾病的病理生理学中的作用。因此，这 工作直接关系到我们对疾病的理解和人类的使命 美国国立卫生研究院。我们提议的研究将为本科生提供 有机会从事严谨和有影响力的科学，并将支持 在阿默斯特学院已经建立了良好的研究环境。