Studies of Signal Transduction by the B-Lymphocyte Antigen Receptor

MCB 9506893 Lawrence J. Stern 本计画将探讨B细胞活化的机制，并结合膜生物化学与蛋白质工程。B细胞构成免疫系统的分支，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细胞被刺激与其他免疫细胞相互作用，并增殖和产生抗体。 触发这一过程的机制知之甚少，但似乎涉及细胞表面受体的聚集。类似的聚集机制激活免疫和神经系统中的其他细胞。细胞膜表面上的这种聚集如何激活细胞内的信号事件尚不清楚。 这种机制的调查一直阻碍了与全细胞系统，特别是，膜结合组件的工作的复杂性。为了更好地理解B细胞活化机制，将开发一个模型系统，在该模型系统中，除了膜之外，还可以研究活化机制的组成部分。 将构建模拟单个受体的B细胞受体的类似物，以及两个、三个和四个受体的簇。 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细胞受体的组成部分上，代替将受体锚在膜上的部分。 不同的模块将以不同大小的簇提供受体的可溶性类似物。 这些簇将用于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传导机制，并有助于我们理解细胞活化过程。 与此研究计划同时，校长Investigat或将执行一个多方面的教育计划。 该计划的一个目标是将创新的计算和分子图形方法引入本科和研究生教育经验。 访问和利用核苷酸和蛋白质数据库中信息的能力已成为一项基本的科学技能。 一个模块将被引入到本科生生物化学实验室，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可视化和操纵蛋白质和核酸的三维结构。 还将探讨利用校园范围的计算机网络来提供补充课程材料以及评价和评估课程内容和介绍。 该教育计划的另一个目标是修订本科生生物化学课程，使学生与影响整个社会的生物化学最新发展保持同步。生物化学入门课程将扩大到包括最近的技术和生物医学的进步，并允许学生批判性地评估医学，法医学，制药，生物技术和当前生物化学研究的其他领域的发展。 本课程还将介绍一门新的蛋白质结构与功能课程。 除了传统的教学活动外，教育计划还为本科生和研究生参与研究项目、社区外展、传统上代表性不足的群体的学生参与、大学预科教育项目以及学生指导和咨询做出了重要规定。 这个项目提供了对调节细胞相互作用方式的机制的深入了解。 细胞之间的相互作用是多细胞生物体形成的基础，也是细胞生物学领域的一个重要问题。 该奖项的教育计划包括将大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，以及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.