Characterization of Conserved Protein Synthesis Aging Pathways

保守蛋白质合成老化途径的表征

• 批准号: 9192920
• 负责人: Hans Martin Dalton
• 金额: $ 4.31万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-01 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9192920
• 关键词: Adult; Affect; Age; Aging; Aging-Related Process; Animal Model; Animals; Binding; Biochemical; Caenorhabditis elegans; Cell Count; Cells; Cessation of life; Clinical; Data; Development; Disease; Disease susceptibility; Gene Expression; Genes; Genetic; Health; Histocompatibility Testing; Human; Hydrogen Peroxide; Injury; Intestines; Lead; Life; Link; Longevity; Longevity Pathway; Modeling; Muscle; Nematoda; Nervous system structure; Neurons; Organism; Oxidative Stress; Pathway interactions; Pattern; Phenotype; Physiological; Process; Protein Biosynthesis; RNA Interference; Reporter; Research; Resistance; Risk; Role; Signal Transduction; Specific qualifier value; Specificity; Staging; Stress; Suppressor Genes; Testing; Time; Tissues; Work; age effect; age related; base; cell type; differential expression; genetic manipulation; insight; intercellular communication; interest; muscular system; mutant; overexpression; pleiotropism; promoter; response; sensory system; spatiotemporal; thermal stress; transcriptome sequencing

All humans age, though the rate of aging is highly variable and likely influenced by one's genetic composition; our cells accumulate damage over time, and this damage can lead to increased disease susceptibility, decreased ability to respond to injury, reduction in sensory systems, among many other detrimental changes. While not necessarily deadly on their own, they lead to a greatly increased risk of death. In order to begin the clinical work in reducing the effects of aging, research must first elucidate the biochemical interactions causing such effects. This project will identify and describe pathways containing conserved longevity-related protein synthesis genes using the model organism, C. elegans. The nematode C. elegans is an excellent model for aging due to its short lifespan, small number of cells, ease of genetic manipulation, and large fraction (>80%) of conserved genes. The reduced expression of protein synthesis genes post-developmentally increases worm lifespan, even up to 50% higher, but the reasons for this lifespan increase are unknown. It has recently been described that reducing protein synthesis cause developmental arrest if given during the larval stage. Given this connection, and multiple previous studies describing similar longevity-related antagonistic pleiotropy, we seek to characterize the protein synthesis pathways involved in both phenotypes; this includes testing the hypothesis that these two phenotypes may use the same pathway as we have recently determined both of these states share a stress resistance phenotype (a metric of increased healthspan). Aim 1 will compile a list of deregulated genes via RNA-seq when worms undergo arrest or longevity in response to reduced protein synthesis. Using this list, and three previously-identified genes that can control the arrest phenotype, we will characterize their spatiotemporal expression patterns, using GFP-bound promoters, and how they correlate with the longevity, arrest, and stress resistance phenotypes. Finally, we will determine if rescuing wild type expression levels of these deregulated genes rescues any of the same phenotypes, indicating their importance in that response. Aim 2 will determine the effects of reducing protein synthesis in a tissue-specific manner (hypodermal, intestinal, muscular, or neuronal) using tissue-specific RNAi strains, which will identify where in the worm the longevity pathway is taking place, including revealing how the signaling and cell-cell crosstalk interacts between cell types to confer longevity, arrest, and stress resistance. The second part of Aim 2 involves coalescing information from our spatiotemporal analysis and tissue-specific studies in order to rescue genes found to be important in conferring these survival-promoting phenotypes in order to determine their importance on a cell or tissue-based level. The description of these protein synthesis genes, particularly in relation to their physiological effects, discovered pathways, and correlation with arrest states and stress resistance, will establish a better connection between enhanced longevity and how that longevity is conferred in order to enable the eventual treatment of aging-related ailments and disease.

所有人都会变老，尽管衰老的速度是高度可变的，很可能受到一个人的基因组成的影响； 随着时间的推移，我们的细胞会积累损伤，这种损伤会导致疾病易感性增加， 对伤害的反应能力下降，感官系统减少，以及许多其他有害的变化。 虽然它们本身不一定是致命的，但它们会导致死亡风险大大增加。为了开始 在减少衰老的临床工作中，研究必须首先阐明导致衰老的生化相互作用 这样的影响。该项目将识别和描述含有保守的长寿相关蛋白的途径。 利用模式生物秀丽线虫合成基因。线虫线虫是一个很好的模型 由于寿命短、细胞数量少、易于遗传操作和比例大(80%)而导致衰老。 保守基因的基因。发育后蛋白质合成基因表达减少会增加蠕虫的数量 寿命，甚至高出50%，但寿命延长的原因尚不清楚。它最近一直在 描述了如果在幼虫阶段给予减少蛋白质合成会导致发育停滞。vt.给出 这一联系，以及之前多项描述类似长寿相关拮抗多效性的研究，我们 寻求表征这两种表型所涉及的蛋白质合成途径；这包括测试 假设这两种表型可能使用与我们最近确定的相同的途径 这些状态具有共同的抗应激表型(延长健康寿命的指标)。AIM 1将编制一份清单， 当蠕虫因蛋白质减少而停止或存活时，通过rna-seq解除调控的基因 综合。利用这份清单，以及之前发现的三个可以控制滞留表型的基因，我们将 利用绿色荧光蛋白结合的启动子，描述它们的时空表达模式，以及它们之间的相互关系 具有长寿、停滞和抗逆性表型。最后，我们将确定是否营救野生型 这些非调控基因的表达水平挽救了任何相同的表型，表明了它们的重要性 在这一回应中。目标2将确定以组织特异性方式减少蛋白质合成的效果 (皮下、肠道、肌肉或神经元)使用组织特定的RNAi菌株，这将识别 蠕虫的长寿途径正在发生，包括揭示信号和细胞间的串扰 在不同类型的细胞之间相互作用，以延长寿命、阻止和抵抗压力。《目标2》的第二部分 将时空分析和特定组织研究的信息结合在一起，以挽救 发现在赋予这些促进生存的表型以确定它们的 在细胞或组织层面上的重要性。对这些蛋白质合成基因的描述，特别是在 与生理效应的关系，发现的途径，以及与停滞状态和应激的关系 抵抗，将在延长寿命和延长寿命的方式之间建立更好的联系 以便能够最终治疗与衰老有关的疾病。