Computational Modeling of Dendritic Cell Maturation

描述(由申请人提供)：树突状细胞(DC)对于发展对一些传染性病原体的保护性免疫是必不可少的。这些细胞提醒适应性免疫系统注意致病入侵者的存在，并激活这些细胞以清除感染。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成熟是一个严格调控的过程，涉及基因表达的变化、细胞内转运、细胞骨架修饰和淋巴器官动员。基因表达网络是基因表达、调控序列和反式作用因子之间相互作用的动态过程，这个过程背后的这个过程对于控制许多观察到的变化非常重要。很少有研究在全面的时间过程中考察这一过程，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了解在感染性因素刺激下DC成熟的生物学基础。我们的目标是确定DC成熟网络的新的、以前未定义的成分，并确定解释DC成熟如何在暴露于各种感染性刺激时受到控制的因果关系。在这个项目中，我们旨在通过三个特定的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集在用PolyI：C作为病毒感染模型治疗DC后的一段时间内DC成熟过程中显著表达的基因来评估DC成熟的动力学。其次，我们的目标是识别显著表达的基因之间的关系，从而开始识别相互作用的网络。最后，我们将演示我们可以识别子网络中涉及的组基因，并对产生的网络邻居进行建模，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，因此更广泛地了解其成熟背后的基因表达程序和全面的转录调控网络是识别新靶点的关键，用于设计和开发针对感染性病原体的疫苗和治疗方法。与公共卫生的相关性：树突状细胞(DC)对于发展对广泛病原体的保护性免疫是必不可少的，并且是疫苗设计的目标。随着我们努力设计更有效的传染病疫苗和治疗方法，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。我们将使用跨学科的方法，结合全球基因表达数据和计算建模，获得DC成熟过程的全面网络模型。

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.