Response to Immune Associated Stress

对免疫相关应激的反应

• 批准号: 10574586
• 负责人: Danielle A Garsin
• 金额: $ 47.89万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-13 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10574586
• 关键词: ATP phosphohydrolase; Address; Affect; Animals; Anti-Inflammatory Agents; Autoimmune Diseases; Bacterial Infections; Caenorhabditis elegans; Chemicals; Communicable Diseases; Complex; Cytoplasm; Cytoprotection; Data; Drug Metabolic Detoxication; Endoplasmic Reticulum Degradation Pathway; Ensure; Exposure to; Family; GATA1 gene; Genes; Genetic Transcription; Goals; Human; Immune; Immune response; Infection; Inflammatory Response; Intestines; Investigation; Knowledge; Laboratories; Lobular Neoplasia; Mammals; Membrane; Modeling; NADPH Oxidase; Orthologous Gene; Oxidative Stress; Pathogenicity; Pathology; Pathway interactions; Patients; Process; Production; Protein Family; Public Health; Publishing; RNA Interference; Reactive Oxygen Species; Regulation; Research; Resistance; Role; Side; Stress; Therapeutic; biological adaptation to stress; innovation; insight; interest; member; novel; nuclear factor-erythroid 2; pathogen; pathogen exposure; pharmacologic; prevent; programs; protective effect; response; trafficking; transcription factor; ATP phosphohydrolase; Address; Affect; Animals; Anti-Inflammatory Agents; Autoimmune Diseases; Bacterial Infections; Caenorhabditis elegans; Chemicals; Communicable Diseases; Complex; Cytoplasm; Cytoprotection; Data; Drug Metabolic Detoxication; Endoplasmic Reticulum Degradation Pathway; Ensure; Exposure to; Family; GATA1 gene; Genes; Genetic Transcription; Goals; Human; Immune; Immune response; Infection; Inflammatory Response; Intestines; Investigation; Knowledge; Laboratories; Lobular Neoplasia; Mammals; Membrane; Modeling; NADPH Oxidase; Orthologous Gene; Oxidative Stress; Pathogenicity; Pathology; Pathway interactions; Patients; Process; Production; Protein Family; Public Health; Publishing; RNA Interference; Reactive Oxygen Species; Regulation; Research; Resistance; Role; Side; Stress; Therapeutic; biological adaptation to stress; innovation; insight; interest; member; novel; nuclear factor-erythroid 2; pathogen; pathogen exposure; pharmacologic; prevent; programs; protective effect; response; trafficking; transcription factor

PROJECT SUMMARY/ABSTRACT Nrf1/2 (human) and SKN-1 (Caenorhabditis elegans ortholog) are key infection-related transcription factors whose regulation is incompletely understood, representing a critical gap in knowledge. The long-term goal of this research is to understand how the host alleviates stress during exposure to pathogens. The objective of this application is to elucidate new mechanisms of SKN-1 regulation that contribute to its protective effects. The central hypothesis is that NIPI-3 and CDC-48.1/2 are amongst previously unknown factors that positively regulate SKN-1 to protect against immune associated stress. The rationale for this investigation is that the identification of new regulators which control a conserved stress response under pathogenic conditions may allow for their therapeutic modulation to alleviate infection induced pathology. The central hypothesis will be addressed by the following aims. Specific Aim #1 will identify how NIPI-3 regulates SKN-1 activity. The working hypothesis, based on preliminary and published data, is that NIPI-3 regulates SKN-1 activity in the intestine via CEBP-1. Specifically, NIPI-3 is proposed to negatively regulate CEBP-1, to directly influence the amount and/or activity of SKN-1 available to carry out its protective transcriptional response. Specific Aim #2 will elucidate the role of CDC-48.1/2 in influencing SKN-1 activity. CDC-48.1/2 is hypothesized to elicit its effects on SKN-1 by its role in the ER-associated degradation (ERAD) pathway. Specifically, it is proposed that CDC-48.1/2 shuttles SKN- 1A, the ER-tethered form of SKN-1, to the cytosolic side of the ER membrane, a process necessary for its activation. However, CDC-48.1/2 is additionally predicted to ensure the proper trafficking of BLI-3, a NADPH oxidase necessary for activating cytoplasmic SKN-1. Specific Aim #3 will identify additional factors that regulate SKN-1 activity and pathogen resistance. In addition to CDC-48.1/2 and NIPI-3, other factors of in- terest were found, including two that only affect SKN-1 activity on pathogen. In this aim, the screen will be com- pleted and additional factors will be characterized. The approach is postulated to reveal further insights into the mechanisms of SKN-1 regulation. Because SKN-1 and human Nrf orthologs protect against infection-related stress, the research will have a significant impact on the understanding of the cytoprotective responses that occur during the immune response. Knowledge of the targets and mechanisms that drive anti-inflammatory re- sponses may allow for their eventual pharmacological targeting for the benefit of those suffering from damaging immune responses. The proposed research is innovative because it identifies SKN-1 regulators under infectious conditions, representing a substantive departure from previous studies.

项目摘要/摘要 NRF1/2（人）和SKN-1（秀丽隐杆线虫直系同源物）是关键感染相关的转录因子 其调节未完全理解，代表了知识的危险差距。这个长期目标 研究是了解宿主在暴露于病原体期间如何减轻压力。这个目的 应用是阐明SKN-1调节的新机制，从而有助于其保护作用。这 中心假设是NIPI-3和CDC-48.1/2是以前未知的因素，这些因素对正面调节 SKN-1防止免疫相关的应激。这项调查的理由是身份证明 在致病条件下控制保守应力反应的新调节器可能允许其 治疗调节以减轻感染诱导的病理。中心假设将由 以下目标。特定目标＃1将确定NIPI-3如何调节SKN-1活性。工作假设， 基于初步和发布的数据，NIPI-3通过CEBP-1调节肠中的SKN-1活性。 具体而言，提议NIPI-3对CEBP-1进行负调节，以直接影响数量和/或活动 SKN-1可用于执行其保护性转录响应。特定目标＃2将阐明 CDC-48.1/2影响SKN-1活性。假设CDC-48.1/2通过其作用引起其对SKN-1的影响 在与ER相关的降解（ERAD）途径中。具体而言，建议CDC-48.1/2 Shuttles skn- 1a，skn-1的ER - 螺旋形式，到ER膜的胞质侧，这是其所需的过程 激活。但是，还可以预测CDC-48.1/2可确保Bli-3的适当贩运 激活细胞质SKN-1所需的氧化酶。特定目标＃3将确定其他因素 调节SKN-1活性和病原体抗性。除了CDC-48.1/2和NIPI-3外，In-的其他因素 发现了Terest，其中包括仅影响病原体SKN-1活性的两个。在此目标中，屏幕将是 杂种和其他因素将被表征。假定该方法是为了揭示对该方法的进一步见解 SKN-1调节的机制。因为SKN-1和人类NRF直系同源物可以防止感染有关 压力，研究将对对细胞保护反应的理解产生重大影响 在免疫反应期间发生。了解驱动抗炎的目标和机制 赞助可能允许其最终的药理学靶向，以便受益于损害的人 免疫反应。拟议的研究具有创新性 条件，代表与以前的研究相去甚远。