Influence of Mutation Burden on Cellular Aging

突变负担对细胞衰老的影响

• 批准号: 8190717
• 负责人: ALAN J HERR
• 金额: $ 7.7万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8190717
• 关键词: Active Sites; Age; Aging; Aging-Related Process; Alleles; Amino Acid Substitution; Animals; Caloric Restriction; Cell Aging; Cell Death; Cell physiology; Cells; Chronic; DNA Polymerase III; DNA biosynthesis; Data; Diploid Cells; Diploidy; Essential Genes; Excision; Extinction (Psychology); Genetic; Haploidy; Heat shock proteins; Homeostasis; Human Genome; Individual; Inherited; Lead; Longevity; Measures; Mismatch Repair; Monitor; Mutagenesis; Mutation; Phenotype; Population; Process; Proteins; Somatic Mutation; Speed; Taxes; Testing; Tissues; Variant; Yeasts; age related; aged; fitness; mutant; oxidative damage; protein aggregate; protein folding; research study; response; tax Gene Products; theories

DESCRIPTION (provided by applicant): As we age, our cells suffer a progressive and permanent loss of genetic information due to the accumulation of mutations. The mounting genetic deficits may limit cellular function or lead to cell death, thereby contributing to the loss of tissue homeostasis that occurs during aging. This proposal seeks to test the influence of mutation burden on aging of diploid yeast. We have evidence that excessive mutation rates can cause extinction of haploid yeast, due to random inactivation of essential genes. In Aim 1 we will define the upper limits of mutation burden for diploids. In Aim 2 we will transiently elevate mutation rates and then measure replicative lifespan, chronological aging, and competitive fitness in the presence and absence of oxidative damage and caloric restriction. In Aim 3, we will monitor cells for altered protein homeostasis as a possible consequence of mutation load. By these studies we hope to establish whether random mutation burden contributes to cellular aging and gain sufficient preliminary data to apply for an R01 to extend our studies into animals. PUBLIC HEALTH RELEVANCE: The somatic mutation accumulation theory of aging posits that the progressive loss of genetic information in our cells leads to declining tissue homeostasis with age. Our preliminary data suggest that high mutation rates can cause extinction of dividing diploid yeast populations. Here we propose to define whether mutation burden enhances aging of diploid yeast.

描述(申请人提供)：随着年龄的增长，由于突变的积累，我们的细胞遭受着遗传信息的渐进性和永久性的丢失。不断增加的遗传缺陷可能会限制细胞功能或导致细胞死亡，从而导致衰老过程中组织动态平衡的丧失。本研究旨在测试突变负荷对二倍体酵母老化的影响。我们有证据表明，由于必需基因的随机失活，过高的突变率会导致单倍体酵母的灭绝。在目标1中，我们将定义二倍体的突变负担上限。在目标2中，我们将暂时提高突变率，然后在存在和不存在氧化损伤和热量限制的情况下测量复制寿命、时间老化和竞争适应性。在目标3中，我们将监测细胞的蛋白质动态平衡变化，这可能是突变负荷的结果。通过这些研究，我们希望确定随机突变负担是否有助于细胞老化，并获得足够的初步数据，以申请R01将我们的研究扩展到动物。 与公共健康相关：衰老的体细胞突变累积理论假设，我们细胞中遗传信息的渐进性丢失导致组织动态平衡随着年龄的增长而下降。我们的初步数据表明，高突变率可能导致二倍体酵母种群的灭绝。在这里，我们建议定义突变负担是否会增强二倍体酵母的老化。