EAGER: Structure-Function Relationships at the Motor Nerve Terminal Active Zone

几十年来，对小龙虾和蜥蜴的神经肌肉突触进行了比较，这让人们普遍接受了突触的结构对其功能几乎没有影响的信条。因此，突触结构-功能关系的研究一直受阻，相反，研究人员将重点放在识别与递质释放和钙信号相关的分子和事件的差异上。在这个项目中，将使用新技术和项目合作者实验室开发的预测计算模型对青蛙和小鼠骨骼肌的神经肌肉连接进行比较研究。这些动物模型提供了几个重要的优势。青蛙和小鼠的神经肌肉接头起着相似的作用(而不是之前研究的在小龙虾和蜥蜴动物模型中起不同作用的突触)，但它们在生理特性和突触前结构和组织上有明显的差异。驱动假说是，神经肌肉突触的关键生理特征是由突触结构的基本构件的结构安排决定的。这项工作将为培养本科生、研究生和研究生以及高中教师提供机会。由于这是一个合作项目，所有受训者都将有独特的机会学习实验和计算方法。重要的是，预计Mcell计算模型将为说明神经末梢结构和功能提供一个前所未有的规模和现实性的例子，有可能真正改变学生对空间和时间中困难的生物化学概念的掌握。该模型还将说明和教授蒙特卡罗模拟、复杂的可视化和动画软件以及各种统计分析方法的使用。

Decades of work comparing neuromuscular synapses in both crayfish and lizards have led to a general acceptance of the dogma that the structure of a synapse has little impact on its function. As a result, the study of structure-function relationships at synapses has been stymied, and, instead, investigators have focused mechanistic studies on the identification of differences in molecules and events associated with transmitter release and calcium signaling. In this project, a comparative study of neuromuscular junctions from frog and mouse skeletal muscle will be carried out using new techniques and a predictive computational model developed in the project collaborators' laboratories. These animal models offer several important advantages. The neuromuscular junctions of frogs and mice serve similar roles (as opposed to previously studied synapses that served different roles in the crayfish and lizard animal models) and yet, have distinct differences in their physiological properties and pre-synaptic structure and organization. The driving hypothesis is that key physiological features of neuromuscular synapses are determined by the structural arrangement of basic building blocks of synaptic structure. This work will offer opportunities for training undergraduate, graduate, and post-graduate students, and high school teachers. Because this is a collaborative project, all trainees will have the unique opportunity to learn both experimental and computational approaches. Importantly, it is expected that the MCell computational model will provide an example of unprecedented scale and realism for the illustration of nerve terminal structure and function with the potential to literally transform a student's grasp of difficult biochemical concepts in space and time. This model will also illustrate and teach the use of Monte Carlo simulations, sophisticated visualization and animation software, and a variety of statistical analysis methods.