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: 8372233
• 负责人: BRIAN K KENNEDY
• 金额: $ 63.68万
• 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/8372233
• 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; Gene Expression Profile; 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

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. PUBLIC HEALTH RELEVANCE: Understanding the pathways that regulate aging is of critical importance to medical research. The field has come to understand that aging is the biggest risk factor in a range of chronic diseases that are principle causes of morbidity and mortality in the United States. Moreover, slowing aging in model organisms does not just extend lifespan but, more importantly, delays the onset and progression of these diseases. In this proposal, a key step forward, we take a comprehensive system-wide approach to understand aging in a commonly studied model organism: yeast. To date, studies in yeast have led in large part to the identification of two pathways (TOR and Sirtuins) that are among the most studied in mammals, lending strength to the hypothesis that the knowledge we gain from studies in yeast will be applicable to human aging.

描述（由申请人提供）：使用无脊椎动物生物已成为衰老研究的中流，从而鉴定出数百个衰老基因。强调这些研究的效用，至少其中一些基因和途径对哺乳动物的寿命有保守的影响。在盘点进度时，很明显，需要采取一种新的，更广泛的方法才能有效前进。如我们所见，需要回答两个主要问题：（1）鉴于有数百个老化基因，其中改变的表达与寿命延长相关，在有机体中，它们代表了多少途径，以及如何划定它们？ （2）在无脊椎动物衰老模型中驱动衰老的机制是什么？后一个问题仍然固执地对衰老研究领域的各种方法固执。为了回答这两个问题，在该提案中，三个具有互补专业知识的研究小组联合起来，通过使用高吞吐量和最先进的方法结合了对酿酒酵母中复制衰老的全面理解。肯尼迪博士（与华盛顿大学的Matt Kaeberlein博士合作）刚刚完成了全基因组ORF敲除基因组屏幕，以增强复制寿命。在AIM 1中，我们将使用肯尼迪实验室的高通量能力来开发最大的上毒网络，以便在功能上评估一组代表性的酵母老化基因中寿命扩展所需的下游途径。在AIM 2中，Li博士的研究小组将使用新开发的微流体系统来确定在长寿命酵母突变体的背景下所涉及衰老的途径状态，并且在AIM 3中，BREM博士的小组将使用RNA测序来开发长寿突变体范围的全面基因表达分析数据集。这两种方法将有助于确定寿命突变体的细胞后果，并通过对AIM 1中的上毒研究进行梳理，我们将对复制性衰老，确定所涉及的途径并朝着对寿命的机械理解方向产生全面的理解。 公共卫生相关性：了解规范衰老的途径对于医学研究至关重要。该领域已经了解到，衰老是一系列慢性疾病的最大危险因素，这是美国发病率和死亡率的主要原因。此外，模型生物的衰老放缓不仅会延长寿命，而且更重要的是，延迟了这些疾病的发作和进展。在此提案中，向前迈出了一个关键的一步，我们采取了一种全面的系统范围的方法来了解常见的模型生物体中的衰老：酵母。迄今为止，在酵母中的研究很大程度上导致了对哺乳动物研究最多的两种途径（Tor和Sirtuins）的鉴定，这是贷款强度，即我们从酵母研究中获得的知识将适用于人类衰老。