Peroxiredoxins, immune signaling and aging.

过氧化还原蛋白、免疫信号传导和衰老。

基本信息

批准号：
8825994
负责人：
Svetlana Nikolaevna Radyuk
金额：
$ 29.23万
依托单位：
SOUTHERN METHODIST UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8825994
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 Health 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

项目摘要

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.

描述（由申请人提供）：拟议研究的长期目标是阐明免疫力与衰老之间的联系。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是有代价的。虽然增强的免疫力可以抵御入侵者，但它可能会对其他有机体功能产生不利影响。免疫效应器可能会对宿主细胞和组织造成损害，最终可能导致功能缺陷。它们还可能对细胞机器提出大量的能量需求，这可能会导致对细胞稳态的维持产生负面影响的权衡。在老年人中，免疫反应对功能和细胞稳态的有害影响进一步加剧，其中适应性免疫下降，先天免疫表现出过度反应和炎症的转变。功能分析表明，老年动物的免疫反应受损，导致反应不足和信号传导受损，进而导致癌症和其他与年龄相关的疾病。如果阐明了正确控制免疫信号的机制，就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和衰老之间相互关系的机制。与老年生物体过度活跃的免疫反应相一致的是向更促氧化的氧化还原状态的变化。我们认为，衰老过程中氧化还原的变化是免疫系统失调的主要因素，并且硫醇依赖性过氧化物酶家族过氧化还原蛋白（peroxiredoxins）被称为氧化还原信号传导的关键调节剂，可能在免疫调节中发挥关键作用。衰老过程中的反应。为了检验过氧化还原蛋白导致老年人免疫应激反应慢性过度激活的假设，我们将采用果蝇模型系统，该系统具有丰富的遗传遗产，具有成熟的调节基因表达的工具。果蝇拥有完整的过氧化物酶，全部具有哺乳动物的直向同源物，此外，果蝇的免疫信号和应激反应途径与哺乳动物中发现的非常相似。我们确定过氧化还原蛋白之一过氧化还原蛋白 5 (dPrx5) 可以调节免疫和应激反应并促进长寿。在拟议的研究中，我们将 i) 确定 dPrx5 调节免疫反应的具体途径并将其定位在这些途径中，ii) 描绘 dPrx5 调节免疫信号传导的分子机制，以及 iii) 确定 dPrx5 调节免疫反应的年龄相关差异。 dPrx5 的免疫信号传导。总之，这些研究应该能够从机制上理解衰老过程中过氧化还原蛋白介导的免疫反应，并建立果蝇寿命和免疫信号之间的关键联系，这将有助于指导高等生物中的类似分析。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Mitochondrial Redox Signaling Is Critical to the Normal Functioning of the Neuronal System.

线粒体氧化还原信号对神经系统的正常功能至关重要。

DOI：
发表时间：
2021
期刊：
影响因子：
0
作者：
Odnokoz, Olena;Nakatsuka, Kyle;Wright, Corbin;Castellanos, Jovelyn;Klichko, Vladimir I;Kretzschmar, Doris;Orr, William C;Radyuk, Svetlana N
通讯作者：
Radyuk, Svetlana N

Mitochondrial peroxiredoxins are essential in regulating the relationship between Drosophila immunity and aging.

线粒体过氧化还原蛋白对于调节果蝇免疫与衰老之间的关系至关重要。

DOI：
发表时间：
2017-01
期刊：
影响因子：
0
作者：
Odnokoz, Olena;Nakatsuka, Kyle;Klichko, Vladimir I;Nguyen, Jacqueline;Solis, Liz Calderon;Ostling, Kaitlin;Badinloo, Marziyeh;Orr, William C;Radyuk, Svetlana N
通讯作者：
Radyuk, Svetlana N

Peroxiredoxins Play an Important Role in the Regulation of Immunity and Aging in Drosophila.

过氧化还原蛋白在果蝇免疫和衰老调节中发挥重要作用。

DOI：
发表时间：
2023-08-15
期刊：
影响因子：
0
作者：
Odnokoz, Olena;Earland, Noah;Badinloo, Marziyeh;Klichko, Vladimir I;Benes, Judith;Orr, William C;Radyuk, Svetlana N
通讯作者：
Radyuk, Svetlana N

Overexpression of antimicrobial peptides contributes to aging through cytotoxic effects in Drosophila tissues.

抗菌肽的过度表达通过果蝇组织中的细胞毒性作用导致衰老。

DOI：
10.1002/arch.21464
发表时间：
2018-08
期刊：
Archives of insect biochemistry and physiology
影响因子：
2.2
作者：
Badinloo M;Nguyen E;Suh W;Alzahrani F;Castellanos J;Klichko VI;Orr WC;Radyuk SN
通讯作者：
Radyuk SN

Hyperoxidation of Peroxiredoxins and Effects on Physiology of Drosophila.

过氧化还原蛋白的过度氧化及其对果蝇生理学的影响。