Lipid regulation of cellular signaling and protein-protein interactions

项目摘要/摘要 细胞信号和蛋白质相互作用的脂质调节 真核细胞可以被视为一种巨大的、广泛划分和分级的蛋白质-- 蛋白质相互作用(PPI)网络。因此，表征PPI是获得 了解细胞的功能。PPI也成为了一个有吸引力的药物靶向空间 发展，因为PPI调节许多细胞过程，如细胞信号。尽管 然而，丰富的PPI数据，复杂的细胞PPI协调和 具有高度时空特异性的调控机制仍然知之甚少。这使得很难 在系统水平上理解细胞调节的机制，也阻碍了 针对PPI的特定药物。在细胞上或细胞附近形成许多PPI网络和蛋白质复合体。 膜，特别是质膜。然而，膜脂类直接参与了 PPI的协调和调制还没有被探索。我们最近在以下方面取得了突破 这一研究路线通过建立直接和 具体调控细胞PPI。这一重要的新发现以及我们创新的现场 定量脂质成像技术给了我们一个独特而无与伦比的机会来系统地 研究不同的脂类如何调节PPI。我们将研究各种脂类， 包括胆固醇和肌醇磷脂，通过以下方式调节多种细胞过程 PPI与蛋白质的特异性相互作用在时空上的协调和调控 相互作用域，包括PDZ域和SH2域。我们还将开发新的小分子 脂依赖的PPI调节剂作为治疗包括癌症在内的各种人类疾病的候选药物。 鉴于购买力平价的普遍和根本重要性，我们的开创性、创新性研究应该 对生物和医学的广泛领域有很高的潜在影响。

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.