Evolution-guided Studies of Mitochondrial Functions

线粒体功能的进化引导研究

• 批准号: 10470887
• 负责人: Dustin Hancks
• 金额: $ 41万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10470887
• 关键词: Autoimmune Diseases; Bioinformatics; Biological; Biological Assay; Biology; Cell physiology; Cells; Characteristics; Cicatrix; Conflict (Psychology); Databases; Dimensions; Electron Transport; Evolution; Genes; Genomics; Host Defense; Host Defense Mechanism; Hypoxia; Immune response; Infection; Invaded; Lead; Link; MicroRNAs; Mitochondria; Modeling; Molecular; Molecular Profiling; Organelles; Outcome; Poxviridae; Production; Proteins; RNA Viruses; Recording of previous events; Regulation; Research; Signal Transduction; Stress; System; TP53 gene; Textbooks; Vaccine Design; Vaccinia; Vesicular stomatitis Indiana virus; Viral; Virus; Virus Diseases; Virus Replication; base; biological adaptation to stress; experimental analysis; gene discovery; gene function; gene product; genetic signature; innovation; novel; novel strategies; programs

PROJECT SUMMARY Although genomics has led to an expansive set of predicted genes, functional annotation of gene products remains rate-limiting. To drive discovery of gene functions, we exploit host-virus interfaces and signatures of conflict. In addition to revealing host defense mechanisms, studies of infected cells and immune responses have led to the definition of fundamental cellular processes and key master regulators (e.g. SRC, P53). Here, we leverage our integrative framework – termed VIROLOG - for the discovery and characterization of novel host- virus interfaces. Specifically, we use genomic scars of conflict unique to factors linked to infection outcomes to identify uncharacterized genes combined with cell-based and viral infection assays. The merit of our strategy is illustrated by the identification of a vertebrate specific MItochondrial STress Response (MISTR) circuit. MISTR is executed by related electron transport chain factors and regulated by ultraconserved miRNAs induced by stress signals such as infection and hypoxia. Using the VIROLOG framework, this research program is defining new battlefronts in mitochondria highlighted by hundreds of viral-encoded factors that may target this organelle during infection to drive viral replication. As our multidimensional bioinformatic screens serve as fertile ground to identify host defenses and uncover new dimensions to textbook functions, we are developing VIROLOG as an interactive user database and interface. Using “classic” viruses such as vaccinia, the prototypical poxvirus, and virus vesicular stomatitis virus (VSV), a model RNA virus, along with the extensive molecular toolkit for key host defenses, we will narrow the gap of genes lacking function. Collectively, our innovative framework continues the rich history of using viral systems to drive biological discovery by exploiting a combination of classic evolutionary and molecular signatures paired with experimental analysis to characterize mechanisms. 1

项目总结