Response to Immune Associated Stress

对免疫相关应激的反应

• 批准号: 9911856
• 负责人: Danielle A Garsin
• 金额: $ 47.59万
• 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/9911856
• 关键词: ATP phosphohydrolase; Address; Affect; Animals; Anti-Inflammatory Agents; Autoimmune Diseases; Bacterial Infections; Caenorhabditis elegans; Centers for Disease Control and Prevention (U.S.); Chemicals; Communicable Diseases; Complex; Data; Endoplasmic Reticulum Degradation Pathway; Ensure; Estrogen receptor positive; Exposure to; Family; Genes; Genetic Transcription; Goals; Human; Immune; Immune response; Infection; Intestines; Investigation; Knowledge; Laboratories; Lobular Neoplasia; Mammals; Membrane; Modeling; NADPH Oxidase; Orthologous Gene; Oxidative Stress; Pathogenicity; Pathology; Pathway interactions; Patients; Pharmacology; Process; Production; Protein Family; Public Health; Publishing; RNA Interference; Reactive Oxygen Species; Regulation; Research; Resistance; Role; Side; Stress; Therapeutic; base; biological adaptation to stress; innovation; insight; interest; member; novel; nuclear factor-erythroid 2; pathogen; pathogen exposure; 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.

项目概要/摘要 Nrf1/2（人）和 SKN-1（秀丽隐杆线虫直系同源物）是关键的感染相关转录因子 其监管尚不完全了解，代表了知识上的重大差距。本次活动的长远目标 研究的目的是了解宿主在接触病原体时如何减轻压力。此举的目的 该应用的目的是阐明有助于其保护作用的 SKN-1 调节新机制。这 中心假设是 NIPI-3 和 CDC-48.1/2 是之前未知的正向调节因子之一 SKN-1 可防止免疫相关压力。这项调查的理由是，鉴定 控制致病条件下保守应激反应的新调节因子可能允许它们 治疗调节以减轻感染引起的病理。中心假设将由 以下目标。具体目标#1 将确定 NIPI-3 如何调节 SKN-1 活性。工作假设， 根据初步和已发表的数据，NIPI-3 通过 CEBP-1 调节肠道中的 SKN-1 活性。 具体而言，NIPI-3 被提议对 CEBP-1 进行负调控，从而直接影响 CEBP-1 的数量和/或活性。 SKN-1 可用于执行其保护性转录反应。具体目标#2 将阐明 CDC-48.1/2 影响 SKN-1 活性。 CDC-48.1/2 被假设通过其作用引发对 SKN-1 的影响 ER 相关降解 (ERAD) 途径。具体来说，建议CDC-48.1/2穿梭于SKN- 1A，SKN-1 的 ER 束缚形式，连接到 ER 膜的胞质侧，这是其发挥作用所必需的过程 激活。然而，CDC-48.1/2 还预计可确保 BLI-3（一种 NADPH）的正确运输 激活细胞质 SKN-1 所必需的氧化酶。具体目标 #3 将确定其他因素 调节 SKN-1 活性和病原体抵抗力。除了CDC-48.1/2和NIPI-3之外，其他影响因素 发现了一些兴趣，其中两个仅影响病原体上的 SKN-1 活性。为了这个目标，屏幕将被 完成后，其他因素将被表征。该方法被认为可以揭示对 SKN-1 的调节机制。因为 SKN-1 和人类 Nrf 直系同源物可防止感染相关的 压力，该研究将对细胞保护反应的理解产生重大影响 发生在免疫反应期间。了解驱动抗炎再治疗的靶点和机制 响应可能允许它们最终的药理学靶向，以造福那些遭受损害的人 免疫反应。拟议的研究具有创新性，因为它确定了传染性下的 SKN-1 调节因子 条件，与之前的研究有实质性的不同。