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

项目总结/摘要 该建议旨在阐明PI（3，4）P2在迁移中的作用机制。 磷脂酰肌醇是细胞信号传导的关键介质。P1（3，4）P2具有 成为细胞迁移的关键调节因子。最近有人提出， Ras和PI（3，4）P2之间的相互抑制反馈回路调节动态 细胞突起的延伸和收缩。本提案将阐明 Ras调节PI（3，4）P2并将PI（3，4）P2确立为善意的机制 与Ras相关的前缘动力学的调节器。我们还将深入了解 PI（3，4）P2在迁移细胞中的调节，通过研究PI- 3激酶PIKF调节网骨藻PI（3，4）P2的生物合成。我们的工作将 还表明PIKF在迁移中的作用归因于其合成能力， PI（3，4）P2。这项工作将提供重要的洞察反馈回路， 调节Ras依赖性活性。这项工作产生的分子工具将是 有助于我们实现阐明联合国系统结构的长期目标， 控制迁移的信令网络。磷脂酰肌醇信号通路在 在细胞信号传导和许多疾病的病理生理学中的作用。因此本 这项工作与我们对疾病的理解和联合国的使命密切相关。 美国国立卫生研究院。我们建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，并将加强 阿默斯特学院已经强大的研究环境。

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.