Studies of Signal Transduction by the B-Lymphocyte Antigen Receptor

MCB 9506893劳伦斯J.斯特恩这个项目研究B细胞激活的机制，并将膜生物化学和蛋白质工程结合在一起。B细胞是免疫系统的一个分支，负责产生针对外来物质的抗体。当外来抗原与B细胞表面的受体结合时，B细胞就会受到刺激，与其他免疫细胞相互作用，并增殖并产生抗体。触发这一过程的机制尚不清楚，但似乎涉及细胞表面受体的聚集。类似的聚集机制激活了免疫和神经系统中的其他细胞。膜表面的这种聚集如何激活细胞内的信号事件尚不清楚。对这一机制的研究一直受到全细胞系统工作的复杂性的阻碍，特别是膜结合组件。为了更好地了解B细胞的激活机制，将开发一个模型系统，在该系统中，除了膜之外，还可以研究激活机制的组成部分。将构建模拟单个受体的B细胞受体的类似物，以及由两个、三个和四个受体组成的簇。对蛋白质基本结构的研究已经确定了以不同组合相互作用的小蛋白质模块。这些模块将被移植到B细胞受体的组件上，而不是将受体固定在膜上的部分。不同的模块将以不同大小的簇提供可溶的受体类似物。这些簇将被用来确定触发信号机制的要求，并研究B细胞受体与其他信号蛋白的相互作用。对B细胞受体及其相互作用的研究将有助于描述这一重要的信号机制，并有助于我们理解细胞激活过程。在此研究计划的同时，校长调查或将执行一个多方面的教育计划。这个项目的一个目标是将创新的计算和分子图形学方法引入本科生和研究生的教育经验中。获取和利用核苷酸和蛋白质数据库中的信息的能力已成为一项基本的科学技能。本科生物化学实验室将引入一个模块，教学生如何访问这些数据库中的信息。另一个模块将包括练习，教学生使用计算机图形工作站来可视化和操作蛋白质和核酸的三维结构。还将探讨如何利用全校范围的计算机网络提供补充课程材料以及评价和评估课程内容和介绍情况。该教育计划的另一个目标是修改本科生物化学课程，使学生跟上影响整个社会的生物化学的最新发展。生物化学入门课程将扩展到包括最新的技术和生物医学进展，并允许学生批判性地评估医学、法医学、药剂学、生物技术和其他当前生化研究领域的发展。还将介绍一门关于蛋白质结构和功能的新课程。除了传统的教学活动外，教育计划还对本科生和研究生参与研究项目、社区推广、传统上代表不足的群体的学生参与、大学前教育项目以及学生指导和咨询等方面做出了重要规定。这个项目提供了对调节细胞相互作用方式的机制的洞察力。细胞间的相互作用是形成多细胞生物体的基础，也是细胞生物学领域的一个重大问题。该奖项的教学计划包括将高分子计算机图形和数据库搜索技术引入本科实验室，扩展生物化学课程，开发创新的教育评估技术。

MCB 9506893 Lawrence J. Stern This project investigates the mechanisms of B-cell activation, and combines membrane biochemistry and protein engineering. B cells comprise the branch of the immune system that is responsible for producing antibodies against foreign material. When a foreign antigen binds to a receptor on the B cell surface, the B cell becomes stimulated to interact with other immune cells, and to proliferate and produce antibodies. The mechanism that triggers this process is poorly understood but appears to involve a clustering of receptors on the cell surface. Similar clustering mechanisms activate other cells in the immune and nervous systems. How such clustering on the membrane surface activates signaling events within the cell is unknown. Investigation of this mechanism has been hampered by the complexity of working with whole-cell systems, and in particular, membrane-bound components. To better understand the B-cell activation mechanism, a model system will be developed in which the components of the activation mechanism can be studied apart from the membrane. Analogues of the B-cell receptor that mimic single receptors, and clusters of two, three, and four receptors, will be constructed. Research into the basic structure of proteins has identified small protein modules that interact in different combinations. These modules will be grafted onto the components of the B-cell receptor in place of the parts that anchor the receptor to the membrane. Different modules will provide soluble analogues of the receptor in different size clusters. These clusters will be used to determine the requirements for triggering the signaling mechanism, and to investigate the interactions of the B-cell receptor with other signaling proteins. Studies of the B-cell receptor and its interactions will contribute to a description of this important signaling mechanism, and to our understanding of cellular activation processes. Concurrent with this research program, the Principal Investigat or will execute a multi-faceted education program. One goal of this program is the introduction of innovative computational and molecular graphic methods into the undergraduate and graduate educational experience. The ability to access and utilize information in nucleotide and protein databases has become an essential scientific skill. A module will be introduced into the undergraduate biochemistry laboratory that teaches students how to access the information in these databases. Another module will comprise exercises that teach students the use of computer graphics workstations to visualize and manipulate protein and nucleic acid structures in three dimensions. The use of a campus-wide computer network to provide supplemental course material and evaluation and assessment of course content and presentation will also be explored. Another goal of the education program is revision of the undergraduate biochemistry curriculum to keep students apace with recent developments in biochemistry that affect society at large. The introductory biochemistry course will be expanded to include recent technological and biomedical advances, and to allow students to critically evaluate developments in medicine, forensics, pharmaceuticals, biotechnology, and other areas of current biochemical research. A new course in protein structure and function also will be introduced. In addition to traditional teaching activities, the education program has important provisions for involvement of undergraduate and graduate students in research projects, community outreach, involvement of students from traditionally under- represented groups, pre-college educational projects, and student mentoring and advising. %%% This project provides insight into mechanisms that regulate the way cells interact. Interactions between cells are the basis for the formation of a multi-cellular organism and a major question in the field of cell biology. The education plan of this award includes the introduction of macromolecular comput er graphics and database search techniques into an undergraduate laboratory, extension of biochemistry curriculum, and development of innovative education assessment techniques.