Lipid regulation of cellular signaling and protein-protein interactions

项目总结/摘要 细胞信号和蛋白质-蛋白质相互作用的脂质调节 真核细胞可以被认为是一个巨大的，广泛区室化和分层的蛋白质- 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也已成为药物治疗的一个有吸引力的靶向空间。 由于PPI调节许多细胞过程，如细胞信号传导，因此PPI是细胞发育的重要因素。尽管 然而，丰富的PPI数据，复杂的细胞PPI协调的机制， 具有高度时空特异性的调节仍然知之甚少。这使得难以 了解细胞调节机制的系统水平，也阻碍了发展， 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。然而，膜脂的直接参与 PPI的协调和调节尚未被探索。我们最近取得了突破性进展， 这一系列的研究，并彻底改变了PPI的研究，建立了脂质直接和 特异性调节细胞PPI。这一重要的新发现以及我们的创新性原位 定量脂质成像技术为我们提供了一个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， 包括胆固醇和磷酸肌醇，调节多种细胞过程， 通过与蛋白质特异性相互作用时空协调和调节PPI 相互作用结构域，包括PDZ和SH 2结构域。我们还将开发新的小分子 脂质依赖性PPI的调节剂作为用于各种人类疾病（包括癌症）的候选药物。 鉴于PPI的普遍和根本重要性，我们的开拓性创新研究应该 对生物学和医学的广泛领域具有很高的潜在影响。

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.