Quantitative Studies of the Immunological Synapse

描述(申请人提供)：细胞之间相互作用，它们的 通过无数膜相关受体和信号传导的环境 分子。除了单个受体-配体结合外，空间 受体重新排列成复杂的模式(突触)正在迅速出现 作为细胞识别的一个重要方面。两个突出的例子， 这项研究的重点是T细胞和NK细胞 免疫突触。私家侦探正在进行一项量化调查 重组项目的体能特征和指导原则 导致了突触的形成。他们开发了一种理论模型，它 与实验观察结果相比较，并表明基本的 免疫突触形成的特征是自发的结果 自组织过程。在这里，他们提议测试和开发这一技术 假设。三管齐下的调查平台，结合了复杂的 新型膜的理论计算和计算机模拟 在重组脂膜和活细胞中的实验，已经被 为满足特定目标而制定的。在目标1中，他们开发了复杂的 理论和计算工具，并使用这些方法和实验 了解T细胞和NK细胞突触的不同形态。在AIM 2，他们对他们的模型进行了稳定性分析，这与 通过实验，将使他们能够研究关键细胞表面参数如何 调节突触的形成。在目标3中，他们确定了监管的影响 细胞内影响突触形成的因素。在Aim 4中，将使用一种基因 算法来探索其他突触模式，并将进行实验以 根据当前的词汇表确定是否可以观察到这样的模式 已知的分子相互作用和细胞类型，或基于合成的 互动。这些研究将提供一个深入和定量的理解 在免疫系统中形成突触模式，并可能导致新的 仿生和治疗方法。

DESCRIPTION (provided by applicant): Cells interact with each other and their environment through myriad membrane associated receptors and signaling molecules. In addition to individual receptor-ligand binding, spatial rearrangement of receptors into complex patterns (synapses) is rapidly emerging as a broadly significant aspect of cell recognition. Two prominent examples, which will be the foci of this investigation, are the T-cell and NK-cell immunological synapses. The PI's are mounting a quantitative investigation of the physical characteristics and principles governing the reorganization events that lead to synapse formation. They have developed a theoretical model, which compares well with experimental observations, and suggests that the essential features of immunological synapse formation are the result of spontaneous self-organization processes. Here, they propose to test and develop this hypothesis. A three-pronged investigative platform, that combines sophisticated theoretical calculations and computer simulations with novel membrane experiments in reconstituted lipid membranes and living cells, has been formulated to meet the specific aims. In aim 1, they develop sophisticated theoretical and computational tools, and use these methods and experiments to understand the differential morphology of T cell and NK cell synapses. In aim 2, they perform a stability analysis of their model and this, in conjunction with experiments, will allow them to study how key cell surface parameters regulate synapse formation. In aim 3, they determine the effects of regulatory factors within the cell on synapse formation. In aim 4, will use a genetic algorithm to explore other synaptic patterns and will perform experiments to determine if such patterns can be observed based on the current vocabulary of known molecular interactions and cell types, or based on synthetic interactions. These studies will provide a deep and quantitative understanding of synaptic pattern formation in the immune system and may lead to novel biomimetic and therapeutic approaches.