Computational Modeling of Dendritic Cell Maturation

树突状细胞成熟的计算模型

• 批准号: 7847578
• 负责人: JACQUELYN Su FETROW
• 金额: $ 18.22万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-22 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7847578
• 关键词: Affect; Biology; Cell Maturation; Cells; Cluster Analysis; Communicable Diseases; Communities; Complex; Computer Simulation; Data; Data Set; Dendritic Cells; Dependency; Development; Drug Formulations; Event; Exposure to; Gene Cluster; Gene Expression; Gene Proteins; Generations; Genes; Genetic; Goals; Graph; Health; Human; IFNAR1 gene; Immune response; Immune system; Immunity; Infection; Infectious Agent; Interferon Receptor; Intracellular Transport; Knock-out; Lymphoid; Maps; Methods; Modeling; Modification; Molecular Profiling; Mus; Nature; Neighborhoods; Network-based; Organ; Outcome; Pattern; Poly I-C; Process; Proteins; Publishing; Sentinel; Signal Pathway; Stimulus; System; Time; Trans-Activators; Transcriptional Regulation; Vaccine Design; Vaccine Therapy; Vaccines; Virus Diseases; base; cohort; design; network models; novel; pathogen; programs; public health relevance; research study; trafficking

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.

描述（由申请人提供）：树突状细胞（DC）对于发展对多种感染性病原体的保护性免疫至关重要。这些细胞向自适应免疫系统提醒病原体入侵者的存在，并激活这些细胞以清除感染。但是，为了刺激这种激活，它们必须经历一种称为成熟的过程，以增加其效力。 DC成熟是一个严格调控的过程，涉及基因表达，细胞内运输，细胞骨架修饰和动员淋巴机器人的变化。基因表达网络，基因表达，调节序列和反式作用因子之间相互作用的动态过程，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课程中检查了这一过程，并且没有人试图得出此过程的网络模型。我们的长期目标是在系统层面上了解传染剂刺激后直流成熟的生物学。我们旨在确定直流成熟网络的新颖，以前未定义的组成部分，并识别出在暴露于各种感染性刺激时如何控制DC成熟的因果关系。在这个项目中，我们旨在通过三个特定目标开发方法并更好地了解DC成熟的基因表达网络。首先，我们将通过识别和聚类基因在DC成熟期间在DC成熟期间在全面的时间过程中用Poly I：C作为病毒感染模型进行DC成熟期间的综合时间过程中显着表达的基因来评估DC成熟的动力学。其次，我们旨在确定显着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，我们将证明我们可以识别涉及子网络中涉及的基因并建模所得的网络社区，从而开始在基因表达网络中建立因果关系与相关关系。由于直流成熟是保护性免疫的关键事件，因此对基因表达程序的更广泛理解以及其成熟的综合转录调节网络是确定新目标的关键，以确定疫苗的设计和开发和针对感染药物的疗法的设计和开发。公共卫生相关性：树突状细胞（DC）对于开发针对广泛病原体的保护性免疫至关重要，并且是针对疫苗设计的。当我们努力为传染病设计更有效的疫苗和疗法时，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。我们将使用跨学科方法与全局基因表达数据结合计算模型，以获得DC成熟过程的全面网络模型。

项目成果

Impact of the Type I Interferon Receptor on the Global Gene Expression Program During the Course of Dendritic Cell Maturation Induced by Polyinosinic Polycytidylic Acid.

• DOI: 10.1089/jir.2014.0150
• 发表时间: 2016-05
• 期刊: Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research
• 作者: Amy L. Olex;William H. Turkett;Kristina L. Brzoza-Lewis;J. Fetrow;E. Hiltbold