Response to Immune Associated Stress

项目摘要/摘要 NRF1/2(人)和SKN-1(秀丽线虫直系物)是感染相关的关键转录因子 其监管还不完全被理解，代表着知识上的严重差距。这样做的长期目标是 研究是为了了解宿主在接触病原体期间如何缓解压力。这样做的目的是 应用是为了阐明SKN-1调节的新机制，这些机制有助于其保护作用。这个 中心假说是NIPI-3和CDC-48.1/2是先前未知的正调控因子 SKN-1，以保护免受免疫相关的压力。这次调查的理由是，身份识别 在致病条件下控制保守的应激反应的新的调节器可能允许他们的 治疗调整，以减轻感染引起的病理。核心假设将由 遵循目标。具体目标1将确定NIPI-3如何调节SKN-1的活性。工作假说， 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。 具体地说，NIPI-3被认为是负调控CEBP-1，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对SKN-1活性的影响。推测CDC-48.1/2通过其作用诱导其对SKN-1的影响 在内质网相关降解(ERAD)途径中。具体来说，建议CDC-48.1/2穿梭SKN-2。 1a，内质网拴系形式的SKN-1，结合到内质网细胞膜的胞质侧，这是其 激活。然而，CDC-48.1/2还被预测为确保NADPH-BLI-3的适当贩运 激活细胞质SKN-1所需的氧化酶。具体目标#3将确定其他因素， 调节SKN-1活性和病原菌抗性。除CDC-48.1/2和NIPI-3外，其他因素- 其中两个仅影响病原菌的SKN-1活性。在这个目标中，屏幕将被- 完整的和额外的因素将被描述。这种方法被认为是为了揭示对 SKN-1的调控机制。因为SKN-1和人类NRF同源基因可以预防感染相关的疾病 应激，这项研究将对理解细胞保护反应产生重大影响 发生在免疫反应过程中。了解推动抗炎再灌流的靶点和机制 海绵可能允许其最终的药理靶向，以造福于那些遭受损害的人。 免疫反应。这项拟议的研究具有创新性，因为它确定了在传染性疾病下的SKN-1调节因子 条件，这与以前的研究有实质性的不同。

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.