MSM: Modeling Spatial Formation of Cellular Components *

MSM：对细胞成分的空间形成进行建模*

• 批准号: 7048746
• 负责人: Teresa L. Head-Gordon
• 金额: $ 29.45万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7048746
• 关键词: T cell receptor; T lymphocyte; antigen presenting cell; biological signal transduction; cell surface receptors; computational biology; cytoskeletal proteins; endocytosis; intermolecular interaction; leukocyte activation /transformation; mathematical model; method development; model design /development; molecular dynamics; protein localization; receptor binding

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.

描述（由申请人提供）： T 细胞激活是适应性免疫反应的基础，了解其调节方式具有许多潜在的好处，包括生产更好的疫苗和治疗自身免疫性疾病。 T 细胞活化取决于 T 细胞受体与抗原呈递细胞上的同源配体的结合。这种相互作用可以刺激细胞内信号级联反应，最终导致基因转录因子的上调。最近，已经证明膜相关分子和细胞内信号传导成分的空间组织在调节 T 细胞信号传导中发挥作用。 T 细胞激活是一种新兴特性，是由涉及多个成分之间相互作用的集体动力学产生的。这种固有的协同性和可以调节集体动态的复杂空间组织使得仅从实验数据中直觉地获得机械见解变得困难，并且进步需要数学模型来整合从分子大小和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跨越多个尺度的具体目标：（1）开发混合分子动力学/布朗动力学方法，该方法将能够研究导致空间介导由受体参与引发的信号传导的多聚蛋白复合物的定位，(2) 开发可以描述由细胞内信号传导触发的细胞骨架动力学以及参与细胞表面受体内吞作用的模型，(3) 开发高效的可以在空间异构和拥挤的分子环境中处理信号反应的随机动力学的算法，并且需要创建结合随机和平均场描述的混合方法。 (4) 虽然上述每一个具体目标都涉及新方法的开发，而新方法本身需要对尺度进行衔接，但我们的第四个具体目标涉及使用具体目标 1 和 2 作为在具体计算中进行计算的必要输入，对尺度进行整体整合。目标 3。例如，将在特定目标 3 中开发的细胞信号动力学模型需要了解多聚体信号复合物是顺序形成还是以协调的方式形成，这将使用特定目标 1 中开发的分子尺度方法来确定。计算结果将直接针对实验进行测试。