Response to Immune Associated Stress

项目总结/摘要 Nrf 1/2（人）和SKN-1（秀丽隐杆线虫直系同源物）是感染相关的关键转录因子 其监管不完全理解，这代表了知识上的重大差距。长期目标是 研究的目的是了解宿主在接触病原体时如何缓解压力。的目的 本申请的目的是阐明有助于其保护作用的SKN-1调节的新机制。的 中心假设是NIPI-3和CDC-48.1/2是以前未知的正调控因子， SKN-1可保护免受免疫相关应激。这项调查的理由是， 在致病条件下控制保守应激反应的新调节因子可能允许它们的 治疗调节以减轻感染引起的病理。中心假设将由 的目标。具体目标#1将确定NIPI-3如何调节SKN-1活性。工作假设， 基于初步和公开的数据，NIPI-3通过CEBP-1调节肠中SKN-1的活性。 具体地，提出NIPI-3负调节CEBP-1，以直接影响CEBP-1的量和/或活性。 SKN-1可用于进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。推测CDC-48.1/2通过其作用引起其对SKN-1的作用， ER相关降解（ERAD）途径。具体来说，有人提出CDC-48.1/2穿梭SKN- 1A，SKN-1的ER栓系形式，与ER膜的胞质侧连接，这是其表达所必需的过程。 activation.然而，另外预测CDC-48.1/2可确保BLI-3（一种NADPH）的适当运输 活化细胞质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活性和病原体抗性。除了CDC-48.1/2和NIPI-3外，其他因素也在... 发现了两个仅影响SKN-1对病原体活性的酶。在这一目标下，屏幕将被... 将表征完整的和附加的因素。该方法被假定为揭示进一步的见解 SKN-1调节机制。因为SKN-1和人类Nrf直系同源物可以防止感染相关的疾病， 压力下，这项研究将对理解细胞保护反应产生重大影响， 发生在免疫反应期间。了解驱动抗炎再发的靶点和机制， sponses可能允许其最终的药理学靶向， 免疫反应。拟议的研究是创新的，因为它确定了SKN-1的监管机构在传染性 条件，这与以前的研究有很大的不同。

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.