Peroxiredoxins, immune signaling and aging.

过氧化还原蛋白、免疫信号传导和衰老。

• 批准号: 8105602
• 负责人: Svetlana Nikolaevna Radyuk
• 金额: $ 30.03万
• 依托单位: SOUTHERN METHODIST UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8105602
• 关键词: Acceleration; Adverse effects; Age; Aging; Animals; Apoptosis; Biological Models; Cell physiology; Cells; Characteristics; Chronic; Complement; Disease; Drosophila genus; Exhibits; Family; Gene Expression; Genes; Genetic; Goals; Homeostasis; Humoral Immunities; Immune; Immune response; Immune system; Immunity; Individual; Inflammation; Intervention; Lead; Link; Longevity; MAPK8 gene; Maintenance; Malignant Neoplasms; Mammals; Measures; Mediating; Modeling; Modification; Molecular; Natural Immunity; Organism; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Peroxidases; Positioning Attribute; Post-Translational Protein Processing; Production; Reading; Regulation; Research; Research Design; Resistance; Role; Signal Pathway; Signal Transduction; Stream; Stress Response Signaling; Sulfhydryl Compounds; Testing; Time; Tissues; adaptive immunity; age related; antimicrobial peptide; biological adaptation to stress; cost; design; fly; immune activation; microbial; middle age; mortality; mutant; peroxiredoxin; peroxiredoxin 5; response; tool

DESCRIPTION (provided by applicant): The long-term goal of the proposed research is to elucidate the connections between immunity and aging. There is mounting evidence that the response and resistance of higher organisms to microbial challenges comes at a cost. While bolstered immunity offers protection against invaders, it may have adverse effects on other organismal functions. Immunity effectors may elicit damage to host cells and tissues, which ultimately could lead to functional deficits. They can also place substantial energy demands on the cellular machinery, which may result in trade-offs that negatively impact the maintenance of cellular homeostasis. The detrimental effects of the immune response on functioning and cellular homeostasis are further exacerbated in older individuals, where adaptive immunity declines and innate immunity exhibits a shift toward an excessive response and inflammation. Functional analyses have established that the immune response is impaired in older animals, resulting in inadequate response and compromised signaling, which in turn can result in cancer and other age-related diseases. If mechanisms of the proper control over immune signaling are elucidated, appropriate interventions can be designed and applied. During the proposed research we will define the mechanisms that govern the inter-relationship between innate immunity and aging. Coincident with the over-active immune response in older organisms is the change to a more pro- oxidizing redox state. We suggest that changes in redox during aging is a major factor in deregulation of the immune system, and that a family of thiol-dependent peroxidases, peroxiredoxins, known as key regulators of redox signaling, are likely to serve critical roles in modulation of the immune response during aging. To test the hypothesis that peroxiredoxins are responsible for chronic over-activation of the immune stress response in older individuals, we will adapt the Drosophila model system, which has a rich genetic heritage with well developed tools for modulating gene expression. Drosophila possesses a full complement of peroxidoxins, all having mammalian orthologues, and furthermore, the immune signaling and stress-response pathways of Drosophila are remarkably similar to those found in mammals. We determined that one of the peroxiredoxins, peroxiredoxin 5 (dPrx5) regulates immune and stress responses and promotes longevity. During the proposed research we will i) determine specific pathways by which dPrx5 modulates the immune response and position it within these pathways, ii) delineate molecular mechanisms, by which dPrx5 modulates immune signaling and iii) determine age-related differences in the regulation of the immune signaling by dPrx5. Together, these studies should permit a mechanistic understanding of peroxiredoxin-mediated immune response during aging and to establish the key links between longevity and immune signaling in the fly, which will help guide similar analyses in higher organisms. PUBLIC HEALTH RELEVANCE: Aging is characterized by malfunctioning of immunity. Deregulation of the immune response during aging can result in cancer and other age-related diseases. The proposed study is aimed at elucidating the mechanisms that underlie such deregulation in order to develop proper interventions.

描述（由申请人提供）：拟议研究的长期目标是阐明免疫与衰老之间的联系。有越来越多的证据表明，高等生物对微生物挑战的反应和抵抗力是有代价的。虽然增强的免疫力为入侵者提供了保护，但它可能会对其他有机体功能产生不利影响。免疫效应子可能会对宿主细胞和组织造成损害，这最终可能导致功能缺陷。他们还可以对细胞机械提出巨大的能量需求，这可能会导致权衡对维持细胞稳态的负面影响。在老年人中，免疫反应对功能和细胞稳态的有害作用进一步加剧，在这种情况下，自适应免疫力下降，先天免疫会向过度反应和炎症转移。功能分析已经确定，在老年动物中，免疫反应受到了损害，导致反应不足和信号传导不足，这又可能导致癌症和其他与年龄有关的疾病。如果阐明了对免疫信号的正确控制的机制，则可以设计和应用适当的干预措施。在拟议的研究中，我们将定义控制先天免疫与衰老之间相互关系的机制。 与较老的生物体中过度活跃的免疫反应一致的是变成更氧化的氧化还原状态。我们认为，衰老过程中氧化还原的变化是免疫系统消耗管制的主要因素，并且一个硫醇依赖性的过氧化物酶（被称为氧化还原信号传导的关键调节剂）家族可能在调节衰老过程中的免疫反应中起关键作用。为了测试过氧化物毒素负责老年人中的免疫应激反应的长期过度激活的假设，我们将适应果蝇模型系统，果蝇模型系统具有丰富的遗传遗产，其具有良好开发的工具可调节基因表达。果蝇具有完全互补的过氧化物毒素，所有果蝇都有哺乳动物直系同源物，此外，果蝇的免疫信号传导和应激反应途径与在哺乳动物中发现的免疫信号传导和应激反应途径非常相似。我们确定一种过氧蛋白之一，过氧蛋白5（DPRX5）调节免疫反应并促进寿命。在拟议的研究中，我们将i）确定DPRX5调节免疫反应并将其定位在这些途径中的特定途径，ii）描绘分子机制，通过该机制，DPRX5通过DPRX5调节免疫信号传导和III）确定与年龄相关的年龄相关差异。总之，这些研究应允许对衰老过程中过氧蛋白介导的免疫反应的机械理解，并在苍蝇中建立寿命和免疫信号传导之间的关键联系，这将有助于指导高等生物体的类似分析。 公共卫生相关性：衰老的特征是免疫力故障。衰老过程中免疫反应的放松管制会导致癌症和其他与年龄有关的疾病。拟议的研究旨在阐明这种放松管制以制定适当干预措施的机制。