Control of Gene Expression and Life Span

基因表达和寿命的控制

• 批准号: 8113179
• 负责人: STEPHEN L HELFAND
• 金额: $ 31.6万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8113179
• 关键词: Affect; Aging-Related Process; Applications Grants; Biochemical; Caloric Restriction; Comparative Study; Data; Drosophila genus; Elements; Gene Expression; Genes; Genetic; Genome; Genomics; Goals; Health; Histones; Human; Intervention; Longevity; Mediating; Modeling; Molecular; Molecular Genetics; Mus; Mutation; Organism; Pathology; Pathway interactions; Physiological; Role; Study Section; System; Testing; Therapeutic Intervention; Translating; age related; base; comparative; dietary restriction; fly; genetic effector; genetic element; overexpression; prevent; therapy development; tool; transcription factor

DESCRIPTION (provided by applicant): Our long-term goal is to understand the genetic and molecular elements that determine the process of aging and life span. The focus of this proposal is to identify molecular genetic effectors that mediate calorie/dietary restriction (CR/DR) life span extension as a prerequisite to developing molecular genetic and pharmacological interventions that can extend healthy life span. Examination of CR/DR in a variety of species shows changes in a large number of genes and physiological systems. A central question in translating this information to therapeutic interventions is which of the many changes seen are involved in extending healthy life span? In flies molecular genetic studies have led to a model in which a portion of the life span extending effect of CR/DR is mediated by alterations in the activity of the histone deacetylases Rpd3 and Sir2, and the transcription factor p53. This model provides a framework for use in identifying genetic, biochemical, and pharmacological effectors of CR/DR mediated longevity. In this proposal we will (i) further examine the mechanisms by which an increase in dSir2 extends life span in the fly, (ii) confirm the life span extending effect of a gene identified through our genomic analysis of the CR/Sir2/p53 pathway and begin to determine it's relationship to CR/DR life span extension, (iii) utilize genome based tools to determine genes and gene sets important for CR/DR life span extension in flies and (iv) test the effect of these newly identified genes on life span using molecular genetic tools. PUBLIC HEALTH RELEVANCE: Calorie/dietary restriction extends life span and delays the onset of age-related pathology in organisms from worms to mice. Understanding the molecular genetic interactions in the calorie/dietary restriction pathway of Drosophila will contribute to the development of interventions to prevent or delay age-dependent decline in humans.

描述（由申请人提供）：我们的长期目标是了解决定衰老和寿命过程的遗传和分子元素。该建议的重点是确定介导卡路里/饮食限制（CR/DR）寿命延长的分子遗传效应子，作为开发可以延长健康寿命的分子遗传和药理干预措施的先决条件。在各种物种中对CR/DR的检查显示了许多基因和生理系统的变化。将这些信息转化为治疗干预措施的一个核心问题是，在延长健康的寿命中所见的许多变化中的哪一个？在苍蝇中，分子遗传研究导致了一个模型，其中一部分寿命延伸的cr/dr的效应是由组蛋白脱乙酰基酶RPD3和SIR2的活性改变以及转录因子p53介导的。该模型为识别CR/DR介导的寿命的遗传，生化和药理学效应子提供了一个框架。在该提案中，我们将（i）进一步研究DSIR2延伸寿命在苍蝇中延长寿命的机制，（ii）确认通过我们对CR/SIR2/p53途径的基因组分析确定的基因的寿命延长了延伸的效果，并开始确定基于Genome spen的跨度和dr sew cr/dr snee gene gene的关系（iii）的关系，（iii sike snece cr/dr seke cr的关系） （iv）使用分子遗传工具测试这些新鉴定的基因对寿命的影响。公共卫生相关性：卡路里/饮食限制延长了寿命，并延迟了从蠕虫到小鼠的生物体中与年龄相关的病理的发作。了解果蝇的卡路里/饮食限制途径中的分子遗传相互作用将有助于开发干预措施，以预防或延迟人类年龄依赖性下降。