MSM: Modeling Spatial Formation of Cellular Components *

描述(由申请人提供)： T细胞激活是适应性免疫反应的基础，了解这种反应是如何调节的有许多潜在的好处，包括生产更好的疫苗和治疗自身免疫性疾病。T细胞的激活取决于T细胞受体与抗原提呈细胞上的同源配体的结合。这种相互作用可以刺激细胞内的信号级联，最终导致基因转录因子的上调。最近的研究表明，膜相关分子和细胞内信号成分的空间组织在调节T细胞信号中起着重要作用。T细胞激活是一种紧急的属性，它是涉及多个组件之间相互作用的集体动力学的结果。这种内在的协作性和复杂的空间组织可以调节集体动力学，使得仅从实验数据直观地获得机械性的见解变得困难，而进步需要数学模型来整合从分子大小、时间尺度到细胞尺度的各种现象。为了解决细胞成分的空间组织如何影响T细胞对外部刺激的反应，我们提出的研究包括四个特定的目标，跨越多个尺度：(1)发展混合分子动力学/布朗动力学方法，使能够研究导致多聚体蛋白质复合体空间定位的动态事件，这些多聚体蛋白质复合体介导由受体参与启动的信号；(2)发展模型，能够描述由细胞内信号触发的细胞骨架动力学和参与细胞表面受体内吞的那些细胞；(3)发展有效的算法，可以处理空间不均匀和拥挤的分子环境中的信号反应的随机动力学，并且需要创建结合随机场和平均场描述的混合方法。(4)虽然上述每个特定目标都涉及到新方法的开发，这本身就需要尺度之间的桥梁，但我们的第四个具体目标涉及使用特定目标1和2作为特定目标3中进行的交配所必需的输入来全面整合尺度。例如，将在特定目标3中开发的细胞信号动力学模型需要知道多聚体信号复合体是顺序形成还是以协调的方式形成，这将使用在特定目标1中开发的分子尺度方法来确定。计算结果将直接与实验进行检验。

DESCRIPTION (provided by applicant): T cell activation underlies the adaptive immune response, and an understanding of how this is regulated has many potential benefits including production of better vaccines and treatment of autoimmune diseases. T cell activation is predicated on the binding of the T cell receptor to cognate ligands on antigen presenting cells. This interaction can stimulate intracellular signaling cascades that ultimately lead to the upregulation of gene transcription factors. Recently, it has been demonstrated that spatial organization of membrane-associated molecules and intracellular signaling components plays a role in regulating T cell signaling. T-cell activation is an emergent property that results from collective dynamics involving interactions between multiple components. This inherent cooperativity and the complex spatial organization that can regulate the collective dynamics makes it difficult to intuit mechanistic insights from experimental data alone, and progress requires mathematical models that integrate phenomena ranging from molecular size and time scales to cellular scales. To address how spatial organization of cellular components influences T cell response to external stimuli, our proposed research includes four specific aims that bridge multiple scales: (1) Develop hybrid Molecular dynamics/Brownian dynamics methods that will enable the study of dynamical events leading to spatial localization of multimeric protein complexes that mediate signaling initiated by receptor engagement, (2) Develop models that can describe cytoskeletal dynamics triggered by intracellular signaling and those involved in endocytosis of cell surface receptors, (3) Develop efficient algorithms that can treat the stochastic dynamics of signaling reactions in a spatially heterogeneous and crowded molecular environment, and will require the creation of hybrid methods combining stochastic and mean-field descriptions. (4) While each of the above specific aims involves the development of new methodology that in itself requires a bridging of scales, our fourth specific aim involves an overall integration of scales using specific aims 1 and 2 as necessary input for the coputations performed in specific aim 3. For example, models of cell signaling dynamics that will be developed in specific aim 3 require knowing whether a multimeric signaling complex forms sequentially or in a concerted fashion, which will be determined using the molecular scale methods developed in specific aim 1. The computational results will be tested directly against experiments.