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

存在于细胞膜内的脂质直接控制许多关键的细胞过程，并且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。一个突出的作用涉及蛋白质-脂质结合相互作用，其中脂质迫使蛋白质募集到细胞膜表面上。这些过程调节蛋白质的功能和定位，导致对许多生理过程的严格控制。尽管具有这种重要意义，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。在这里，提出了全面的战略，以克服这些挑战，并解开这些复杂的结合相互作用的细节。所提出的研究的一个方面涉及对应于重要信号脂质的化学探针的设计和合成。在这里，模块化的合成策略将被设计用于在许多生物学研究中使用的一系列探针结构的有效生成。此外，Best小组将开发表征脂质生物活性的新方法。一种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膜结合的细节的快速检测。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性的变化，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，以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，提高对科学研究价值的认识。例如，来自当地高中的学生将在他们的实验室进行研究，并展示海报来展示他们的结果。此外，PI将在学校科学院的会议上发表演讲，向学生介绍科学研究所取得的令人兴奋的进步。此外，最佳集团将与当地中学教师合作，使研究生将参加实验室课程，以加强这些会议。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好理解。

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.