System approaches to determine mechanisms underlying yeast replicative aging

确定酵母复制老化机制的系统方法

• 批准号: 8724849
• 负责人: BRIAN K KENNEDY
• 金额: $ 5万
• 依托单位: BUCK INSTITUTE FOR RESEARCH ON AGING
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8724849
• 关键词: Affect; Age; Aging; Aging-Related Process; Animal Model; Automobile Driving; Biological Aging; Biological Markers; Biological Process; Cells; Chronic Disease; Collaborations; Collection; Comb animal structure; Complex; Coupled; Data; Data Set; Disease; Disease Progression; Elements; Ensure; Event; Eye; Gene Deletion; Gene Expression Profile; Gene Expression Profiling; Genes; Genetic; Genetic Epistasis; Genetic Transcription; Goals; Human; Imagery; Individual; Invertebrates; Knock-out; Knowledge; Life; Link; Longevity; Longevity Pathway; Mammals; Medical Research; Methodology; Microfluidics; Microscopy; Modeling; Molecular; Morbidity - disease rate; Mothers; Mutation; Open Reading Frames; Organism; Pathway interactions; Pattern; Phenotype; Population; Proteins; RNA; RNA Sequences; Refractory; Regulation; Relative (related person); Research; Risk Factors; Saccharomyces cerevisiae; Series; Sirtuins; Statistical Methods; Study models; Surveys; System; Systems Biology; Testing; Time; Translations; United States; Universities; Washington; Yeasts; aging gene; base; biological adaptation to stress; daughter cell; design; genome wide association study; insight; molecular marker; molecular phenotype; mortality; mutant; research study; transcriptome sequencing

DESCRIPTION (provided by applicant): The use of invertebrate organisms has become a mainstay of aging research, leading to the identification of hundreds of aging genes. Emphasizing the utility of these studies, at least some of these genes and pathways have conserved effects on longevity in mammals. In taking stock of the progress, it is clear that a new, more system wide approach is required to effective move forward. As we see it, there are two main questions that need to be answered: (1) Given that there are hundreds of aging genes, in which altered expression is associated with lifespan extension, in an organism, how many pathways do they represent and how can they be delineated?; (2) what are the mechanisms that drive aging in invertebrate aging models and are they conserved? This latter question has remained stubbornly refractory to a variety of approaches in the aging research field. With an eye toward answering these two questions, in this proposal three research groups with complementary expertise have joined forces to develop a comprehensive understanding of replicative aging in Saccharomyces cerevisiae using a combination of high throughput and state-of-the-art approaches. Dr. Kennedy (in collaboration with Dr. Matt Kaeberlein at the University of Washington) has just completed a genome-wide screen of yeast ORF knockouts for enhanced replicative lifespan. In Aim 1, we will develop the largest epistasis network of aging using the high-throughput capacity of the Kennedy lab to functionally assess which downstream pathways are required for lifespan extension in a set of representative yeast aging genes. In Aim 2, Dr. Li's research group will use a newly developed microfluidic system to determine the state of pathways purported to be involved in aging in the context of long-lived yeast mutants and in Aim 3, Dr. Brem's group will use RNA sequencing to develop a comprehensive gene expression analysis dataset in a range of long-lived mutants. These latter two approaches will help determine the cellular consequences of longevity mutants and by combing those with the epistasis studies in Aim 1, we will generate a comprehensive understanding of replicative aging, identifying the pathways involved and moving toward a mechanistic understanding of longevity.

描述（由申请人提供）：无脊椎动物的使用已成为衰老研究的支柱，导致数百种衰老基因的鉴定。强调这些研究的实用性，至少其中一些基因和途径对哺乳动物的寿命具有保守的影响。在评估进展时，很明显需要采取新的、更广泛的系统方法来有效向前推进。我们认为，有两个主要问题需要回答：（1）考虑到有机体中有数百个衰老基因，其中表达改变与寿命延长相关，它们代表了多少条通路以及如何描述它们？ （2）无脊椎动物衰老模型中驱动衰老的机制是什么？它们是否保守？后一个问题对于衰老研究领域的各种方法来说仍然顽固地难以解​​决。为了回答这两个问题，在本提案中，三个具有互补专业知识的研究小组联手，结合高通量和最先进的方法，全面了解酿酒酵母的复制衰老。 Kennedy 博士（与华盛顿大学的 Matt Kaeberlein 博士合作）刚刚完成了酵母 ORF 敲除的全基因组筛选，以延长复制寿命。在目标 1 中，我们将利用肯尼迪实验室的高通量能力开发最大的衰老上位网络，以功能性地评估一组代表性酵母衰老基因中延长寿命所需的下游途径。在目标 2 中，李博士的研究小组将使用新开发的微流体系统来确定长寿酵母突变体中据称与衰老有关的通路的状态；在目标 3 中，Brem 博士的研究小组将使用 RNA 测序来开发一系列长寿突变体的综合基因表达分析数据集。后两种方法将有助于确定长寿突变体的细胞后果，并通过将这些结果与目标 1 中的上位性研究相结合，我们将对复制衰老产生全面的理解，确定所涉及的途径并朝着对长寿的机械理解迈进。