Simulation of Lymphocyte Adhesion using Integrated Adhesive Dynamics

描述（由申请人提供）：T淋巴细胞归巢的集成多尺度粘附动力学建模丹尼尔A。放大图片作者：Hammer（PI），加里T. Koretzky（co-PI）项目概述免疫系统的正常功能依赖于免疫细胞（如T淋巴细胞）在全身旅行并返回专门组织以传递分子信息的能力。细胞之间的密切分子通讯对免疫细胞的成熟和激活至关重要。已经确定，淋巴细胞从血流和淋巴组织的运输是由分子“邮政编码”控制的，该邮政编码识别淋巴细胞需要行进的精确位置。邮政编码是淋巴细胞和宿主组织上的粘附分子和趋化因子/趋化因子受体对的组合，使得当存在“匹配”时，淋巴细胞可以通过快速粘附来响应。该提案的目标是开发新的计算工具，以了解淋巴细胞如何整合和转换分子信号，激活白细胞整合素介导流动下的特异性粘附。这些工具的基础是整合信号转导网络，无论是涉及G蛋白的趋化因子激活或组装的“信号体”，到粘附动力学，细胞粘附的模拟器。这种综合方法可以很容易地预测淋巴细胞的牢固粘附率。研究的主要问题是，多种趋化因子信号如何整合在一个单一的网络中，信号体如何组装和增强整合素和粘附强度，以及淋巴细胞粘附的时间尺度如何依赖于淋巴细胞表面受体的分子密度和身份。我们将对淋巴细胞停止的速率进行预测，并与Jurkat细胞和小鼠原代T细胞的粘附测量进行比较。我们将利用分子工程来敲除或表达这些细胞系中的信号成分，并进行相应的模拟来验证我们的方法的准确性。净结果将是一种新的计算工具，能够预测淋巴细胞粘附的位置。公共卫生相关性：T淋巴细胞归巢的集成多尺度粘附动力学建模丹尼尔A。放大图片作者：Hammer（PI），加里T. Koretzky（co-PI）相关性为了执行其免疫功能，淋巴细胞必须前往体内的特定位置。淋巴细胞亚系的归巢是通过复杂的分子邮政编码控制的，其中淋巴细胞上的表面受体结合血管壁上的配体，并且分子密码的组合导致归巢的保真度。目前还不清楚淋巴细胞如何通过内部信号转导网络整合分子信息，以决定在哪里粘附。这项建议的目标是建立一个计算框架，用于模拟粘附和淋巴细胞信号转导之间的相互作用，以更好地了解控制淋巴细胞归巢的因素。

DESCRIPTION (provided by applicant): Integrated Multi-scale Adhesive Dynamics Modeling of T-lymphocyte Homing Daniel A. Hammer (PI), Gary T. Koretzky (co-PI) Project Summary The proper functioning of the immune system relies on the ability of immune cells such as T-lymphocytes to travel throughout the body and home to specialized tissues to transfer molecular information. Intimate molecular communication between cells is crucial to immune cells' maturation and activation. It has been established that lymphocyte trafficking from the blood stream and the lymphatic tissues is controlled by molecular "zip-codes" that identify the precise location where lymphocytes need to travel. The zip-code is the combination of adhesion molecules and chemokines/chemokine receptor pairs on the lymphocyte and host tissue, such that when there is a "match", the lymphocyte can respond by adhering rapidly. The goal of this proposal is to develop novel computational tools to understand how lymphocytes integrate and convert molecular signals into the activation of leukocyte integrins to mediate specific adhesion under flow. The basis of these tools is the integration of signal transduction networks, either involving chemokine activation of G-proteins or the assembly of a "signalsome', into Adhesive Dynamics, a simulator of cell adhesion. This integrated method can readily predict the rate of lymphocyte firm adhesion. The main questions of investigation are, how are multiple chemokine signals integrated within a single network, how does the signalsome assemble and reinforce integrin and adhesion strength, and how does the time-scale for lymphocyte adhesion depend on molecular density and identity of lymphocyte surface receptors? We will make predictions on the rate of lymphocyte stopping, and compare to measurements of adhesion for Jurkat cells and primary T-cells from mice. We will make use of molecular engineering to knock down or express signaling components within these cell lines, and perform corresponding simulations to verify the accuracy of our methods. The net result will be a novel computational tool with the ability to predict the location of lymphocyte adhesion. PUBLIC HEALTH RELEVANCE: Integrated Multi-scale Adhesive Dynamics Modeling of T-lymphocyte Homing Daniel A. Hammer (PI), Gary T. Koretzky (co-PI) Relevance To carry out their immunological function, lymphocytes must travel to specific locations within the body. The homing of lymphocyte sublines is controlled through a complex molecular zip- coding, in which surface receptors on lymphocytes bind ligands on blood vessel walls, and the combination of molecular codes leads to the fidelity of homing. It is not understood how lymphocytes integrate molecular information through internal signal transduction networks to make decisions on where to adhere. The goal of this proposal is to develop a computational framework for modeling the interplay between adhesion and lymphocyte signal transduction to gain a better understanding of the factors that control lymphocyte homing.