Lipid regulation of cellular signaling and protein-protein interactions

细胞信号传导和蛋白质-蛋白质相互作用的脂质调节

• 批准号: 9898389
• 负责人: WONHWA CHO
• 金额: $ 60.96万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9898389
• 关键词: Area; Binding Proteins; Biology; Cell membrane; Cell physiology; Cells; Cholesterol; Complex; Data; Development; Drug Targeting; Eukaryotic Cell; Imaging technology; In Situ; Lipids; Malignant Neoplasms; Medicine; Membrane Lipids; Phosphatidylinositols; Proteins; Regulation; Research; Signal Transduction; Signaling Protein; Specificity; System; cell growth regulation; drug candidate; drug development; human disease; innovation; insight; protein complex; protein protein interaction; public health relevance; small molecule; spatiotemporal; src Homology Region 2 Domain

PROJECT SUMMARY/ABSTRACT Lipid regulation of cellular signaling and protein-protein interactions Eukaryotic cells can be regarded as a vast, extensively compartmentalized and hierarchic protein- protein interaction (PPI) network. Characterizing PPI is therefore a crucial step in gaining an understanding of how cells function. PPI has also emerged as an attractive target space for drug development since PPI regulates numerous cellular processes, such as cell signaling. Despite the wealth of PPI data, however, the mechanisms by which complex cellular PPIs are coordinated and regulated with high spatiotemporal specificity are still poorly understood. This makes it difficult to understand the mechanisms of cell regulation on a systems level and also hampers development of specific drugs targeting PPI. Many PPI networks and protein complexes are formed on or near the cell membranes, the plasma membrane in particular. However, direct involvement of membrane lipids in coordination and modulation of PPI has not been explored. We have recently made breakthroughs in this line of research and revolutionized the PPI research by establishing that lipids directly and specifically regulate cellular PPI. This important new discovery as well as our innovative in situ quantitative lipid imaging technology give us a unique and unparalleled opportunity to systematically investigate how various lipids modulate PPI. We will study the mechanisms by which various lipids, including cholesterol and phosphoinositides, regulate a wide variety of cellular processes by spatiotemporally coordinating and modulating PPI through their specific interaction with protein interaction domains, including PDZ and SH2 domains. We will also develop new small molecule modulators of lipid-dependent PPI as drug candidates for various human diseases, including cancer. Given the general and fundamental importance of PPI, our pioneering, innovative research should have high potential impact on broad areas of biology and medicine.

项目摘要/摘要 细胞信号传导和蛋白质蛋白相互作用的脂质调节 真核细胞可被视为广泛的，广泛的分隔和分层蛋白 蛋白质相互作用（PPI）网络。因此，表征PPI是获得的关键步骤 了解细胞的功能。 PPI也已成为药物的吸引人目标空间 由于PPI调节了许多细胞过程，例如细胞信号传导。尽管有 但是，PPI数据的财富，但是，复杂的细胞PPI是协调的机制，并且 受高时空特异性的调节仍然很少了解。这使得很难 了解系统级别的细胞调节机制，也妨碍 针对PPI的特定药物。许多PPI网络和蛋白质复合物在细胞上或附近形成 膜，尤其是质膜。但是，膜脂质直接参与 尚未探讨PPI的协调和调制。我们最近在 这一研究线并通过直接确定脂质并彻底改变了PPI研究 特别调节细胞PPI。这一重要的新发现以及我们的创新现场 定量脂质成像技术为我们提供了独特而无与伦比的机会 研究各种脂质如何调节PPI。我们将研究各种脂质的机制， 包括胆固醇和磷酸肌醇，通过 通过与蛋白质的特异性相互作用，空间时空协调和调节PPI 相互作用域，包括PDZ和SH2域。我们还将开发新的小分子 脂质依赖性PPI的调节剂是包括癌症在内的各种人类疾病的药物候选者。 鉴于PPI的一般和根本重要性，我们的开创性，创新的研究应该 对生物学和医学的广泛领域具有很大的潜在影响。