Computational Modeling of Dendritic Cell Maturation

描述（由申请人提供）：树突状细胞（DC）是发展对许多感染性病原体的保护性免疫所必需的。这些细胞向适应性免疫系统发出病原入侵者的警报，并激活这些细胞来清除感染。然而，为了刺激这种激活，它们必须经历一个称为成熟的过程，以增加它们的效力。DC成熟是一个受严格调控的过程，涉及基因表达、细胞内运输、细胞骨架修饰和淋巴器官动员的变化。这一过程背后的基因表达网络，即基因表达、调控序列和反式作用因子之间相互作用的动态过程，对控制许多观察到的变化至关重要。很少有研究在一个全面的时间过程中检验这一过程，也没有人试图推导出这一过程的网络模型。我们的长期目标是在系统水平上理解在感染因子刺激下DC成熟的生物学基础。我们的目标是确定新的，以前未定义的DC成熟网络的组成部分，并确定因果关系，解释在暴露于各种感染刺激时如何控制DC成熟。在本项目中，我们的目标是通过三个具体目标来开发方法并更好地了解DC成熟背后的基因表达网络。首先，我们将通过鉴定和聚I:C作为病毒感染模型处理DC后在DC成熟过程中显著表达的基因并将其聚类来评估DC成熟的动态。其次，我们的目标是确定显著表达的基因之间的关系，从而开始确定相互作用的网络。最后，我们将证明我们可以识别子网络中涉及的基因组，并对所产生的网络邻域进行建模，从而开始在基因表达网络中建立因果关系和相关关系。由于DC成熟是保护性免疫的关键事件，因此更广泛地了解基因表达程序和其成熟背后的综合转录调控网络是确定设计和开发针对感染因子的疫苗和治疗的新靶点的关键。公共卫生相关性：树突状细胞（DC）对于发展针对多种病原体的保护性免疫至关重要，并且是设计疫苗的目标。了解这些细胞被激活或“成熟”的过程对人类健康具有重要意义，因为我们正在努力设计更有效的传染病疫苗和治疗方法。我们将采用跨学科的方法，结合全球基因表达数据和计算建模来获得DC成熟过程的综合网络模型。

DESCRIPTION (provided by applicant): Dendritic cells (DC) are essential to the development of protective immunity to a number of infectious pathogens. These cells alert the adaptive immune system to the presence of pathogenic invaders and activate these cells to clear infections. To stimulate such activation, however, they must undergo a process termed maturation that increases their potency. DC maturation is a tightly regulated process involving changes in gene expression, intracellular trafficking, cytoskeletal modifications, and mobilization to lymphoid organs. The gene expression network, the dynamic process of interaction among gene expression, regulatory sequences, and trans-acting factors, underlying this process is extremely important for controlling many of the observed changes. Very few studies have examined this process over a comprehensive time course and none have attempted to derive network models of this process. Our long-term goal is to understand, at a systems level, the biology that underlies DC maturation following stimulation by infectious agents. We aim to identify novel, previously undefined components of the DC maturation network and to identify cause-and-effect relationships that explain how DC maturation is controlled upon exposure to various infectious stimuli. In this project, we aim to develop methods and obtain a better understanding of the gene expression network underlying DC maturation through three specific aims. First, we will assess the dynamics of DC maturation by identifying and clustering genes that are significantly expressed during DC maturation over a comprehensive time course following treatment of DC with poly I:C as a model of viral infection. Second, we aim to identify relationships between significantly expressed genes, thus beginning to identify networks of interactions. And finally, we will demonstrate that we can identify groups genes involved in sub-networks and model the resulting network neighborhoods, thus beginning to establish cause-and-effect versus correlative relationships within the gene expression network. Because DC maturation is such a pivotal event for protective immunity, a broader understanding of the gene expression program and the comprehensive transcriptional regulatory network underlying their maturation is a key to the identification of new targets for the design and development of vaccines and therapies against infectious agents. Public Health Relevance: Dendritic cells (DC) are essential to the development of protective immunity to a broad range of pathogens and are being targeted in the design of vaccines. Understanding the process through which these cells are activated or "matured" is of great significance to human health as we endeavor to design more effective vaccines and therapies for infectious diseases. We will use a cross-disciplinary approach with global gene expression data combined with computational modeling to gain a comprehensive network model of the process of DC maturation.