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元素。这项计划的目的是测试特定的基因和蛋白质如何影响热量限制下的寿命延长。热量限制的研究显示了大量基因和生理系统的变化。其中之一，Rpd 3/Sir 2途径，已涉及在酵母，线虫和苍蝇的寿命延长。通过控制热量限制/Rpd 3/Sir 2通路来开发延长寿命的分子遗传学和药理学干预措施的先决条件是更好地理解该通路及其调控的基因和蛋白质。在本提案中，我们将确认Sir 2在果蝇热量限制通路中的重要性，确定Sir 2在该通路中相对于Rpd 3的位置，确定其对长寿作用的重要组织的时间和部位，并检查已知增加Sir 2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，我们将研究在寿命延长的作用p53，转录因子和肿瘤抑制因子在哺乳动物中的活动是由Sir 2控制。最后，我们将使用比较微阵列分析，以确定基因和蛋白质的重要影响寿命的Rpd 3/Sir 2/热量限制途径的苍蝇，并启动潜在的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.