Stochastic aspects of aging (5 of 11)

衰老的随机方面（11 中的 5）

• 批准号: 7753009
• 负责人: JAN VIJG
• 金额: $ 42.82万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7753009
• 关键词: Adult; Age; Aging; Aging-Related Process; Animals; Area; Bacteria; Binding; Biochemical Genetics; Biological; Biological Models; Biological Process; Buffers; Cell model; Cell physiology; Cells; Cellular Stress; Cellular Stress Response; Characteristics; Computer information processing; Data; Development; Dimensions; Disease; Drosophila genus; Employee Strikes; End Point; Energy Metabolism; Environment; Environmental Risk Factor; Epigenetic Process; Event; Evolution; Fibroblasts; Functional disorder; Gene Expression; Genes; Genetic; Genome; Genomics; Human; Individual; Individual Differences; Laboratories; LacZ Genes; Longevity; Malignant Neoplasms; Mammals; Measurable; Measures; Messenger RNA; Methods; Modeling; Molecular; Monitor; Mus; Mutation; Nature; Nematoda; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Noise; Numbers; Organism; Outcome; Output; Oxidative Stress; Pathology; Pathway interactions; Pattern; Phenotype; Physiological; Population; Process; Proteins; Range; Rate; Reporter; Reporter Genes; Research; Role; Signal Transduction; Stem cells; System; Testing; Time; Transcript; Variant; Work; Yeasts; age related; cell type; concept; disease phenotype; driving force; experience; fitness; fly; functional status; interdisciplinary approach; response; stem; stressor; tool

All biological systems are subject to stochastic variation. In mammals this is obvious from the large individual variation in life span and patterns of aging-related pathology, even in genetically homogeneous animals. Stochasticity is also apparent at the molecular level. Random molecular fluctuations creating variability in gene expression within a cell population have been demonstrated in bacteria and yeast. To some extent this is inherent to the nature of the processes of information transfer, especially at small numbers of mRNA or protein products per cell. However, noise at the molecular level can also have external causes, varying from random damage to the genome to variability in regulatory signals. While sometimes advantageous, i.e., in development and evolution, increased Stochasticity in aging is generally viewed as having detrimental effects on cellular function. The central hypothesis in this proposal is that oxidative stress, a likely cause of aging, increases stochastic variability of gene expression, that it does so by causing both genetic and epigenetic changes in cells, and that cells and organisms possess a variety of genetic pathways and cellular responses to mitigate or buffer against unduly large stochastic changes. We will test this hypothesis in two specific aims. First, we will comparatively analyze four different model systems of aging, nematodes, fruit flies, mice and human cells, for mutation accumulation at a similar lacZ reporter construct. We will also investigate how such genome level Stochasticity depends on genetic factors known to cause aging-related neurodegenerative disease, how it differs between human and mouse cells and how it can be modulated by genetic factors. Second, we will directly measure transcriptional noise levels in mouse neurons and neuronal stem cells during aging and in model systems for human neurodegenerative diseases. In parallel, we will study similar transcriptional noise in human and mouse fibroblasts in different genetic backgrounds and among individual nematodes during aging. We expect that the proposed study will provide a new dimension to existing paradigms in the field by defining the role of Stochasticity in aging phenotypes and identifying the genetic and biochemical mechanisms that influence it.

所有的生物系统都受到随机变化的影响。在哺乳动物中，这一点从大型个体 寿命的变化和与衰老相关的病理模式，即使在遗传同质的动物。 随机性在分子水平上也很明显。随机的分子波动造成了 在细菌和酵母中已经证实了细胞群体内的基因表达。这在一定程度上 是信息传递过程的本质所固有的，特别是在少量的mRNA或 每个细胞的蛋白质产物。然而，分子水平上的噪声也可能有外部原因， 基因组的随机损伤到调节信号的变异性。虽然有时是有利的，即，在 发展和进化，增加随机性在老龄化通常被视为具有不利影响 对细胞功能的影响。这项提议的核心假设是，氧化应激，一个可能导致衰老的原因， 增加了基因表达的随机变异性，它通过引起遗传和表观遗传 细胞的变化，细胞和生物体具有多种遗传途径和细胞反应 以减轻或缓冲过大的随机变化。我们将在两个具体的实验中验证这一假设。 目标。首先，我们将比较分析线虫、果蝇、小鼠四种不同的衰老模型系统 和人细胞，用于在类似的lacZ报告构建体处的突变积累。我们还将研究如何 这种基因组水平的随机性取决于已知引起衰老相关的遗传因素 神经退行性疾病，它在人类和小鼠细胞之间的差异以及它如何被调节 遗传因素其次，我们将直接测量小鼠神经元和神经元中的转录噪声水平。 衰老过程中的干细胞和人类神经退行性疾病的模型系统。同时，我们将 在不同遗传背景的人类和小鼠成纤维细胞中研究类似的转录噪音， 在衰老过程中发生的变化。我们希望拟议的研究将提供一个新的层面， 通过定义随机性在衰老表型中的作用，并确定 基因和生化机制的影响。