Control of Gene Expression and Life Span

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因素。本提案的重点是确定介导卡路里/饮食限制（CR/DR）延长寿命的分子遗传效应，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。多种物种的CR/DR检测显示了大量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，所看到的许多变化中，哪些与延长健康寿命有关？在果蝇中，分子遗传学研究已经建立了一个模型，其中CR/DR的部分寿命延长效应是由组蛋白去乙酰化酶Rpd3和Sir2以及转录因子p53活性的改变介导的。该模型为识别CR/DR介导的长寿的遗传、生化和药理学效应提供了一个框架。在本提案中，我们将(i)进一步研究dSir2增加延长果蝇寿命的机制，（ii）确认通过我们对CR/Sir2/p53通路的基因组分析发现的基因的寿命延长作用，并开始确定它与CR/DR寿命延长的关系。（iii）利用基于基因组的工具确定对延长果蝇CR/DR寿命重要的基因和基因集；（iv）使用分子遗传学工具测试这些新发现的基因对寿命的影响。公共卫生相关性：限制卡路里/饮食可以延长寿命，并延缓从蠕虫到老鼠等生物体中与年龄相关的病理的发生。了解果蝇热量/饮食限制途径中的分子遗传相互作用将有助于开发预防或延缓人类年龄依赖性衰退的干预措施。

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.