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。这项提议的目的是测试特定的基因和蛋白质如何影响卡路里限制下的寿命延长。对卡路里限制的研究表明，大量基因和生理系统发生了变化。其中之一，Rpd3/Sir2途径，已被认为与酵母、线虫和苍蝇的寿命延长有关。通过操纵热量限制/Rpd3/Sir2途径来开发延长寿命的分子遗传和药物干预措施的先决条件是更好地了解该途径及其调控的基因和蛋白质。在这项建议中，我们将确认Sir2在果蝇热量限制途径中的重要性，确定Sir2在该途径中相对于Rpd3的位置，确定对其长寿起重要作用的组织的时间和位置，并检查已知增加Sir2活性的小外源分子对长寿的影响。使用我们的苍蝇模型系统，我们将研究P53在延长寿命中的作用，P53是哺乳动物中的一种转录因子和肿瘤抑制因子，其活性受Sir2控制。最后，我们将使用比较微阵列分析来确定在果蝇Rpd3/Sir2/卡路里限制途径中影响寿命的重要基因和蛋白质，并启动潜在效应分子的遗传分析。

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 aim of this proposal is to test how specific genes and proteins affect the life span extension seen with caloric restriction. Studies of caloric restriction show changes in a large number of genes and physiological systems. One of these, the Rpd3/Sir2 pathway, has been implicated in life span extension in yeast, nematodes, and flies. A prerequisite to developing molecular genetic and pharmacological interventions that extend life span through the manipulation of the caloric restriction/Rpd3/Sir2 pathway is a better understanding of the pathway and the genes and proteins that are regulated by it. In this proposal we will confirm the importance of Sir2 in the caloric restriction pathway in flies, define the position of Sir2 within the pathway relative to Rpd3, determine the timing and site of tissues important for its action on longevity, and examine the effect of small exogenous molecules known to increase Sir2 activity on longevity. Using our fly model system we will then examine the role in life span extension of p53, a transcription factor and tumor suppressor in mammals whose activity is controlled by Sir2. Finally, we will use a comparative microarray analysis to identify genes and proteins important in effecting longevity in the Rpd3/Sir2/caloric restriction pathway in flies and initiate a genetic analysis of the potential effector molecules.