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: 7113671
• 负责人: Teresa L. Head-Gordon
• 金额: $ 26.27万
• 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/7113671
• 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细胞活化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益处，包括生产更好的疫苗和治疗自身免疫性疾病。T细胞活化基于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，最终导致基因转录因子的上调。最近，它已被证明，空间组织的膜相关分子和细胞内的信号成分在调节T细胞信号中发挥作用。T细胞活化是一种涌现的性质，其由涉及多个组分之间相互作用的集体动力学引起。这种固有的协同性和复杂的空间组织可以调节集体动力学，这使得很难从实验数据中直观地了解机械的见解，进步需要数学模型，这些模型可以整合从分子大小和时间尺度到细胞尺度的现象。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，这些目标可以连接多个尺度：（1）开发混合分子动力学/布朗动力学方法，其将使得能够研究导致多聚体蛋白质复合物的空间定位的动力学事件，所述多聚体蛋白质复合物介导由受体接合引发的信号传导，（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和参与细胞表面受体内吞作用的细胞骨架动力学的模型，（3）开发可以处理空间异质和拥挤分子环境中信号传导反应的随机动力学的有效算法，并且将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到新方法的开发，而新方法本身就需要尺度的桥接，但我们的第四个具体目标涉及到尺度的整体整合，使用具体目标1和2作为具体目标3中执行的接合的必要输入。例如，将在具体目标3中开发的细胞信号传导动力学模型需要知道多聚体信号传导复合物是顺序形成还是以协同方式形成，这将使用具体目标1中开发的分子尺度方法来确定。计算结果将直接通过实验进行检验。