CAREER: Chemical Approaches to the Investigation of Protein-Lipid Binding

存在于细胞膜内的脂质直接控制着许多关键的细胞过程，脂质组成和活性的缺陷导致许多使人衰弱的疾病，包括癌症和糖尿病。一个突出的作用与蛋白质-脂质结合相互作用有关，在这种相互作用中，脂质强制将蛋白质招募到细胞膜表面。这些过程调节蛋白质的功能和定位，从而严格控制许多生理过程。尽管具有这种意义，但由于研究生物膜内发生的事件的固有挑战，蛋白质-脂质结合的许多方面仍然知之甚少。本文提出了克服这些挑战的综合策略，并揭示了这些复杂结合相互作用的细节。提出的研究的一个方面涉及设计和合成化学探针对应的重要信号脂质。在这里，模块化的合成策略将被设计为有效地产生一系列探针结构，用于众多的生物学研究。此外，Best小组将开发新的方法来表征脂质的生物活性。其中一个这样的策略是微阵列分析，其中采用不同格式和条件的高通量技术将导致快速检测膜结合的细节。除了回答有关这些过程的重要问题外，这些平台还将用于检测正常和疾病相关系统之间脂质活动的变化，以研究这些化合物在疾病中的作用。最后，将开发一种基于探针的方法来实现选择性纯化和鉴定与复杂细胞提取物中特定脂质相互作用的蛋白质。最佳小组将与当地学校的教师和学生合作，以提高对科学研究优点的认识。例如，来自当地一所高中的学生将在他们的实验室进行研究，并展示一张海报来展示他们的成果。此外，PI还将在学校科学院的会议上发表演讲，向学生们介绍科学研究取得的令人兴奋的进展。此外，Best小组将与当地中学教师合作，以便研究生参加实验课程，以加强这些课程。通过这些努力，他们将把他们的研究扩展到当地社区，以培养对科学研究的更多理解。

Lipids present within cell membranes directly control many critical cellular processes, and defects in lipid composition and activity result in a number of debilitating diseases, including cancer and diabetes. A prominent role pertains to protein-lipid binding interactions, in which lipids enforce the recruitment of proteins onto the surfaces of cellular membranes. These processes regulate both protein function and localization, resulting in tight control over numerous physiological processes. Despite this significance, many aspects of protein-lipid binding remain poorly understand due to the inherent challenges of studying events that occur within biological membranes. Herein, comprehensive strategies are proposed to surmount these challenges and unravel the details of these complex binding interactions. One aspect of the proposed research involves the design and synthesis of chemical probes corresponding to important signaling lipids. Here, modular synthetic strategies will be devised for efficient generation of a range of probe structures for use in numerous biological studies. In addition, the Best group will develop novel approaches for characterizing the biological activities of lipids. One such strategy is that of microarray analysis, in which high-throughput techniques employing different formats and conditions will result in rapid detection of the details of membrane binding. In addition to answering important questions about these processes, these platforms will also be used to detect variations in lipid activities between normal and disease-associated systems to study the roles of these compounds in disease. Finally, a probe-based approach will be developed to achieve selective purification and identification of proteins that interact with a particular lipid from complex cell extracts. The Best group will partner with teachers and students at local schools to increase awareness of the merits of scientific research. For example, students from a local high school will perform research in their laboratory and present a poster to showcase their results. In addition, the PI will make presentations at meetings of the school's science academy to inform students about the exciting advancements that result from scientific research. Further, the Best group will partner with local middle school teachers such that graduate students will participate in laboratory courses to enhance these sessions. Through these efforts, they will extend their research to the local community to cultivate a greater understanding of scientific research.