A novel computational model of B cell signaling and activation

描述(申请人提供)：我们实验室的长期目标之一是开发不同的分析和计算机模拟技术，并将其结合到一个统一的计算模拟方案中，以研究B细胞的反应。我们在Silico模型中提出了这一点，专门研究B细胞免疫识别、信号传递和激活的机制。计算建模将以迭代的方式与生物实验协同进行。我们的模型的随机性使我们能够捕捉到系统中存在的任何细胞到细胞的随机波动。我们严格地将我们模型的概率参数映射到生物实验中可测量的反应和扩散速率常数。这项拟议的工作将提供以下内容：(I)分别针对膜结合抗原和可溶性抗原以免疫突触和帽的形式研究B细胞受体聚集的计算和理论方法；(Ii)与单分子跟踪研究并行的异质B细胞膜中受体扩散的计算机模型；(Iii)B细胞信号的计算模型，B细胞免疫学家可以使用该模型通过在电子实验中控制运行来研究在大量不同生理条件下的B细胞抗原识别、信号传递和激活。我们的方法还将能够通过识别亲和力差异很大的抗原来解决B细胞如何产生分级反应的问题。 公共卫生相关性：B细胞免疫反应是一个复杂的过程，仅从体内和体外实验研究B细胞信号和激活的精确机制并不容易。在这项拟议的研究中，我们计划开发B细胞抗原识别、信号传递和激活的计算机模型。我们的计算机模型将有助于阐明B细胞免疫反应的基本调节机制，并可能被应用于研究B细胞介导的疾病。

DESCRIPTION (provided by applicant): One of the long-term goals of our laboratory is to develop and combine different analytical and computer simulation techniques into a unified computational modeling scheme to investigate B cell responses. We are developing this proposed in silico model specifically to investigate the mechanism of B cell immune recognition, signaling, and activation. Computational modeling will be carried out synergistically with biological experiments in an iterative manner. The stochastic character of our model enables us to capture any cell-to-cell stochastic fluctuations present in the system. We rigorously map the probabilistic parameters of our model to the reaction and diffusion rate constants that are measurable in biological experiments. This proposed work is going to deliver the following: (i) computational and theoretical approaches to investigate B cell receptor clustering in the form of immune synapses and caps for the cases of membrane-bound and soluble antigens respectively, (ii) a computer model of receptor diffusion in a heterogeneous B cell membrane in parallel with single molecules tracking studies, (iii) a computational model of B cell signaling that can be used by B cell immunologists to study B cell antigen recognition, signaling, and activation under a plethora of different physiological conditions by running controlled in silico experiments. Our approach will also be able to address the question of how B cells generate a graded response by recognizing antigens of widely varying affinities. PUBLIC HEALTH RELEVANCE: The B cell immune response is a complex process and a precise mechanism of B cell signaling and activation is not easy to investigate from in vivo and in vitro experiments alone. In the proposed research, we plan to develop computer models of B cell antigen recognition, signaling, and activation. Our computer model will help elucidate the fundamental regulation mechanisms underlying the B cell immune response and could potentially be applied to investigate B cell mediated diseases.