Systems-biology Approaches for Decoding Persistent Coxsackievirus B3 Infection

解码持续性柯萨奇病毒 B3 感染的系统生物学方法

基本信息

批准号：
8511124
负责人：
Kevin A Janes
金额：
$ 23.39万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-03-01 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8511124
关键词：
ATF2 gene Acute Address Affect Agonist Architecture Biochemical Biological Assay Biological Models CREB1 gene Cardiac Myocytes Cardiotoxicity Caspase Cell Death Cells Child Chronic Chronic Phase Cleaved cell Coxsackie Viruses Coxsackievirus Infections Cytokine Signaling Data Disease Event Feedback Gene Expression Genes Genome Goals Half-Life Heart Heart Transplantation Heart failure In Vitro Infection Infiltration Inflammation Inflammatory Intervention Least-Squares Analysis Link Lymphocyte Lytic Phase MAPK14 gene MAPK8 gene Measurement Measures Mediator of activation protein Messenger RNA Methods Modeling Molecular Monitor Myocarditis Myocardium Pathogenesis Pathway interactions Patients Phase Phosphoric Monoester Hydrolases Phosphotransferases Play Polyproteins RNA RNA Stability Recombinants Regulation Role Route Signal Pathway Signal Transduction Staging Stimulus Structural Protein System Systems Biology Technology Testing Time Tissues Transcript Translating Untranslated Regions Up-Regulation Viral Virus Virus Diseases Work base combinatorial computerized data processing cytokine design fascinate insight mRNA Decay mathematical model method development new therapeutic target novel outcome forecast pathogen public health relevance reconstitution response transcription factor viral RNA young adult

项目摘要

DESCRIPTION (provided by applicant): Coxsackievirus B3 (CVB3) is a leading cause of chronic heart inflammation and heart failure in children and young adults. Persistent CVB3 infection is not associated with the mature virus but instead with latent expression of its RNA genome in cardiomyocytes. Our preliminary observations suggest that the presence of CVB3 RNA disrupts how cardiomyocytes normally respond to inflammatory stimuli, which may be important for establishing a chronically inflamed state. The objective of this proposal is to defin the molecular "rewiring" that takes place in cardiomyocytes upon chronic infection with CVB3. Our hypothesis is that persistent expression of CVB3 RNA disrupts the posttranscriptional signaling response of cardiomyocytes to proinflammatory stimuli. During the R21 phase, we will develop high-throughput biochemical methods to measure signaling and transcript stability at the systems level. In the R33 phase, these assays will be combined to examine posttranscriptional signal processing in cultured cardiomyocytes expressing CVB3 RNA and stimulated with proinflammatory cytokines. The data will ultimately serve as the basis for a computational-systems model that connects signaling events to gene expression and transcript stability. Aim #1 of the R21 phase is to develop quantitative, systems-level bioassays to measure kinase-phosphatase activation in cardiomyocytes chronically infected with CVB3. Aim #2 of the R21 phase is to develop a real-time, multiplex RNA stability assay for profiling half-lif regulation of NF-?B transcripts in cardiomyocytes. Aim #3 of the R33 phase is to interrogate intracellular dynamics triggered by proinflammatory cytokines and build a predictive, data-driven systems model that captures CVB3-induced cardiomyocyte rewiring. The long-term goal is to use the model to propose novel interventions that can correct posttranscriptional signal processing in patients with persistent CVB3 infection.

描述（由申请人提供）：柯萨奇病毒 B3 (CVB3) 是儿童和年轻人慢性心脏炎症和心力衰竭的主要原因。持续的 CVB3 感染与成熟病毒无关，而是与其 RNA 基因组在心肌细胞中的潜在表达有关。我们的初步观察表明，CVB3 RNA 的存在扰乱了心肌细胞对炎症刺激的正常反应，这对于建立慢性炎症状态可能很重要。该提案的目的是定义慢性感染 CVB3 后心肌细胞中发生的分子“重新布线”。我们的假设是，CVB3 RNA 的持续表达会破坏心肌细胞对促炎刺激的转录后信号反应。在R21阶段，我们将开发高通量生化方法来测量系统水平的信号传导和转录稳定性。在 R33 阶段，这些测定将结合起来检查表达 CVB3 RNA 并用促炎细胞因子刺激的培养心肌细胞的转录后信号处理。这些数据最终将作为计算系统模型的基础，将信号事件与基因表达和转录稳定性联系起来。 R21 阶段的目标#1 是开发定量的系统级生物测定法，以测量慢性感染 CVB3 的心肌细胞中的激酶磷酸酶激活情况。 R21 阶段的目标#2 是开发一种实时、多重 RNA 稳定性测定，用于分析心肌细胞中 NF-κB 转录本的半衰期调节。 R33 阶段的目标#3 是探究促炎细胞因子触发的细胞内动力学，并建立一个预测性、数据驱动的系统模型来捕获 CVB3 诱导的心肌细胞重新布线。长期目标是利用该模型提出新的干预措施，以纠正持续 CVB3 感染患者的转录后信号处理。