Characterizing the impacts of a novel environmental contributor on ROS hormesis and aging in C. elegans

表征新型环境贡献者对线虫 ROS 兴奋作用和衰老的影响

• 批准号: 10471330
• 负责人: Jennifer L Thies
• 金额: $ 6.29万
• 依托单位: UNIVERSITY OF ALABAMA IN TUSCALOOSA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10471330
• 关键词: 5' -AMP-activated protein kinase; Address; Affect; Age; Aging; Animal Model; Animals; Bacteria; Binding Sites; Bioinformatics; Biological Assay; Biological Process; Caenorhabditis elegans; Candidate Disease Gene; Cells; Chronic; Data; Defect; Development; Disease; Dose; Environmental Risk Factor; Exhibits; Exposure to; Financial Hardship; Fluorescence; Genes; Genetic; Health; Healthcare Systems; Human; IGF-1 Signaling Pathway; Impairment; Insulin; Insulin Signaling Pathway; Knowledge; Life; Longevity; MAPK8 gene; Measures; Mediating; Messenger RNA; Mitochondria; Molecular; Molecular Profiling; Morphology; Nematoda; Nerve Degeneration; Neurotoxins; Oxidative Stress; Oxidoreductase; Pathway interactions; Pattern; Phenotype; Population; Process; Production; Protein Kinase; Reactive Oxygen Species; Regulation; Reporter; Reporting; Signal Pathway; Signal Repression; Signal Transduction; Signaling Molecule; Societies; Soil; Source; Streptomyces; Stress; Up-Regulation; Well in self; age related; biological adaptation to stress; caregiving; combat; differential expression; dopaminergic neuron; gene product; healthspan; healthy aging; improved; in vivo; insight; insulin signaling; interest; mutant; nervous system disorder; novel; protein function; proteotoxicity; response; transcription factor; transcriptomics

Project Summary/Abstract As the average age of the global population continues to rise, finding strategies to promote not only longevity, but healthspan, is critical. For example, aging is a major factor in the development and progression of many neurological disorders, and it increases the financial burden on healthcare systems, presenting new challenges within our society for caregiving and emotional wellbeing. In this regard, there is much interest in determining whether healthy aging can be enhanced. Our lab has identified an environmental factor that has a hormetic effect on both lifespan and neurodegeneration in the nematode model organism, Caenorhabditis elegans (C. elegans). When nematodes are chronically exposed to higher concentrations (20X) of this environmental factor, they have shorter lifespans and exhibit neurodegeneration of dopaminergic neurons. Conversely, when chronically exposed to low concentrations (5X), they live longer and do not display neurodegeneration. The factor we discovered is a secreted metabolite produced by the common soil bacterium Streptomyces venezuelae (S. ven). Similar to many substances that display hormetic responses, I have determined that this metabolite functions via the transcription factor DAF-16/FOXO. This transcription factor regulates longevity through the activation or repression of signaling molecules associated with oxidative stress responses. In this proposal, I will utilize C. elegans to further investigate the differences in the aging process following exposure to high (20X) and low (5X) concentrations of the S. ven metabolite. Aim 1 seeks to investigate hormetic ROS induction following exposure to different concentrations of S. ven metabolite. This will be addressed via a) Quantifying cellular alterations by examining differences in ROS levels using in vivo and ex vivo assays and b) Investigating the impact of S. ven metabolite on ATP levels. I hypothesize 5X S. ven metabolite will cause mild ROS induction that is beneficial to C. elegans, while 20X will do the opposite. In Aim 2, I will examine a DAF- 16-dependent longevity response. The mechanism underlying the hormetic response will be sought using aging analyses and qPCR on differentially expressed genes (DEGs) from a prior transcriptomic analysis. I previously identified 20 DEGs associated with daf-16 and/or daf-2; of which several are associated with oxidoreductase processes that I am interested in further pursuing. I hypothesize that the hormetic response is impacting the insulin/IGF-1 signaling pathway to confer the extended lifespan phenotype observed when worms are exposed to 5X metabolite. I also propose that the metabolite is altering the expression of DAF-16- dependent genes, particularly DEGs involved in oxidoreduction processes thus impacting longevity. Ultimately, defining a molecular signature of this hormetin will illustrate signaling pathways influenced by a previously identified neurotoxin, and could provide a promising approach for the identification of treatment targets for age- related disorders.

项目概要/摘要 随着全球人口平均年龄持续上升，寻找策略不仅可以延长寿命， 但健康寿命至关重要。例如，衰老是许多疾病发展和进展的主要因素。 神经系统疾病，增加了医疗保健系统的经济负担，带来了新的挑战 在我们的社会中提供护理和情感健康。在这方面，人们对确定 是否可以促进健康老龄化。我们的实验室已经确定了一种具有毒物兴奋作用的环境因素 对线虫模型生物秀丽隐杆线虫寿命和神经变性的影响 （线虫）。当线虫长期暴露于较高浓度 (20X) 的环境中时 因素，它们的寿命较短，并且表现出多巴胺能神经元的神经变性。相反，当 长期暴露于低浓度（5X），它们的寿命更长并且不会表现出神经退行性变。这 我们发现的因子是常见土壤细菌链霉菌产生的分泌代谢物 委内瑞拉 (S. ven)。与许多表现出毒物兴奋反应的物质类似，我确定这 代谢通过转录因子 DAF-16/FOXO 发挥作用。这种转录因子调节寿命 通过激活或抑制与氧化应激反应相关的信号分子。在这个 建议，我将利用秀丽隐杆线虫进一步研究接触后衰老过程的差异 S. ven 代谢物的高 (20X) 和低 (5X) 浓度。目标 1 寻求研究激效活性氧 (ROS) 暴露于不同浓度的S.ven代谢物后的诱导。这将通过 a) 解决 通过使用体内和离体测定检查 ROS 水平的差异来量化细胞变化，b) 研究 S. ven 代谢物对 ATP 水平的影响。我假设 5X S. ven 代谢物会导致轻度 ROS 诱导对线虫有利，而 20X 则相反。在目标 2 中，我将检查 DAF- 16 依赖性长寿反应。将使用以下方法寻找毒物兴奋反应的潜在机制： 对先前转录组分析中的差异表达基因 (DEG) 进行老化分析和 qPCR。我 先前鉴定出与 daf-16 和/或 daf-2 相关的 20 个 DEG；其中有几个与 我有兴趣进一步研究氧化还原酶过程。我假设毒物兴奋反应是 影响胰岛素/IGF-1信号通路以赋予观察到的延长寿命表型 蠕虫暴露于 5X 代谢物。我还认为该代谢物正在改变 DAF-16- 的表达 依赖基因，特别是参与氧化还原过程的DEG，从而影响寿命。最终， 定义这种激素的分子特征将说明受先前的影响的信号传导途径 确定了神经毒素，并且可以为确定年龄相关的治疗目标提供一种有前途的方法。 相关疾病。

项目成果

Xanthine Dehydrogenase Is a Modulator of Dopaminergic Neurodegeneration in Response to Bacterial Metabolite Exposure in C. elegans.

黄嘌呤脱氢酶是线虫细菌代谢物暴露反应中多巴胺能神经变性的调节剂。

• 发表时间: 2023-04-15
• 影响因子: 6
• 作者: Thies, Jennifer L;Willicott, Karolina;Craig, Maici L;Greene, Madeline R;DuGay, Cassandra N;Caldwell, Guy A;Caldwell, Kim A
• 通讯作者: Caldwell, Kim A