Control of Gene Expression and Life Span

描述(由申请者提供)：我们的长期目标是了解决定衰老过程和寿命的遗传和分子因素。这项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，作为开发能够延长健康寿命的分子遗传和药物干预的先决条件。对多种物种的CR/DR检测表明，大量的基因和生理系统发生了变化。将这一信息转化为治疗干预措施的一个中心问题是，在所看到的许多变化中，哪些涉及延长健康寿命？在果蝇中，分子遗传学研究导致了一种模型，在该模型中，CR/DR延长寿命的一部分是通过组蛋白脱乙酰酶Rpd3和Sir2以及转录因子P53的活性变化来介导的。该模型为识别CR/DR介导的长寿的遗传、生化和药理效应提供了一个框架。在这项建议中，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途径的基因组分析而确定的基因的寿命延长效果，并开始确定其与CR/DR寿命延长的关系，(Iii)利用基于基因组的工具来确定对果蝇CR/DR寿命延长至关重要的基因和基因集，以及(Iv)利用分子遗传学工具测试这些新发现的基因对寿命的影响。与公共卫生相关：限制卡路里/饮食可延长寿命，并延缓从蠕虫到老鼠的生物体中与年龄有关的疾病的发生。了解果蝇卡路里/饮食限制途径中的分子遗传相互作用将有助于开发预防或延缓人类年龄相关性衰退的干预措施。

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.