Research Project 2: Role of Posttranscriptional Regulatory Networks in the Pathogenesis of Ebola Virus Disease

研究项目2：转录后调控网络在埃博拉病毒疾病发病机制中的作用

• 批准号: 10602493
• 负责人: Mariano A. Garcia-Blanco
• 金额: $ 34.54万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10602493
• 关键词: Address; Affect; Antisense Oligonucleotides; Area; Bioinformatics; Candidate Disease Gene; Cell physiology; Cells; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Data; Data Analyses; Dendritic Cells; Development; Ebola Hemorrhagic Fever; Ebola virus; Endothelial Cells; Event; Filovirus; Gene Expression; Genes; Hepatitis C; Hepatocyte; Human; Immune; Immune Tolerance; Immune response; Infection; Investigation; Knowledge; Literature; Massive Parallel Sequencing; Mediating; Methods; Modeling; Modification; Molecular; Pathogenesis; Pathogenicity; Pathway interactions; Phenotype; Post-Transcriptional Regulation; Protein Isoforms; Publishing; RNA; RNA Interference; RNA Processing; RNA Splicing; RNA-Binding Proteins; Regulation; Regulator Genes; Research Project Grants; Role; Sampling; T cell response; T-Lymphocyte; Testing; Tissues; Transcription Process; Translations; Viral; Viral Pathogenesis; Virus; Virus Diseases; Virus Replication; Work; candidate identification; cell type; data resource; experimental study; exposed human population; in vivo; insight; kidney cell; knock-down; knowledge integration; mRNA Translation; monocyte; nonhuman primate; novel; posttranscriptional; programs; proteogenomics; response; therapeutic RNA; transcription regulatory network; transcriptome; virtual

RESEARCH PROJECT 2 (RP2): PROJECT SUMMARY/ABSTRACT This overall Program Project seeks to address a significant knowledge gap concerning Ebola virus (EBOV): how infection leads to a pathogenic rather than protective immune response. In this project, the focus is on how EBOV infection alters posttranscriptional gene regulation in critical immune cell types and in cells that are heavily infected (e.g., hepatocytes). There is limited understanding of how EBOV infection impacts host gene expression at the posttranscriptional level. Indeed, although the importance of posttranscriptional regulation in gene expression for multiple pathogenic human viruses is evident, this level of regulation has been understudied for filoviruses. The central hypothesis of Research Project 2 (RP2) is that cell type-specific and gene-specific posttranscriptional responses in EBOV disease contribute to the maladaptive phenotypes of immune cells, eventually leading to “immune paralysis” and hyperinflammation. To address this hypothesis, we will characterize the posttranscriptional landscape during EBOV infections of primary human immune and nonimmune cells. We will decipher the influence of EBOV infection on host RNA processing and translation. Massively parallel sequencing approaches made possible by the Proteogenomics Core (Core C) will be used to define RNA processing events, RNA modifications, and mRNA translation efficiency transcriptome-wide in naïve and infected cells. Importantly, samples generated from the same experiments in the BSL-4 Core (Core B) will be used by all three projects and thus we plan to compare our data with that of RP1 and RP3. Data analysis, integration, and modelling will be performed in collaboration with the Bioinformatics and Modeling Core (Core D). These experiments will yield new insights into the effect of EBOV infection on cellular gene expression in relevant cell types. We will also characterize the posttranscriptional landscape during EBOV infection in vivo in nonhuman primates. Using the data from these experiments, with Core D we will construct a comprehensive model of regulated host pathways that modulate EBOV infection in different immune cell types. This model will identify candidate genes that represent important nodes for these pathways and thus potential vulnerabilities for EBOV. In collaboration with Core B, this project will validate posttranscriptionally altered genes and events, and ask whether they are functionally important to cell-type specific responses to EBOV infection. Completion of this project will reveal new and underappreciated layers of host responses to EBOV infection, and provide a rich data resource for the field that will lead to new hypotheses to address the molecular basis for EBOV pathogenesis. Moreover, we will identify critical new host and/or viral targets that can be exploited to disrupt the pathogenicity of this deadly virus.

研究项目2 (rp2)：项目摘要/摘要