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Stochastic aspects of aging (5 of 11)

衰老的随机方面（11 中的 5）

基本信息

批准号：
7872846
负责人：
JAN VIJG
金额：
$ 39.15万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
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/7872846
关键词：
Adult Age Aging Aging-Related Process Animals Area Bacteria Binding Biochemical Biological Models Biological Process Buffers Cell model Cell physiology Cells Cellular Stress Cellular Stress Response Characteristics Data Development Dimensions Disease Drosophila genus Employee Strikes 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 Organism Outcome Output Oxidative Stress Pathology Pathway interactions Pattern Phenotype Physiological Population Process Proteins Reporter Reporter Genes Research Role Signal Transduction Stem cells Testing Time Transcript Variant Work Yeasts age related biological systems cell type disease phenotype driving force experience fitness fly functional status information processing interdisciplinary approach response stem stressor tool

项目摘要

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，从大型个体来看，这一点很明显