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。这项提议的目的是测试特定的基因和蛋白质如何影响热量限制所带来的寿命延长。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，Rpd3/Sir2通路，与酵母菌、线虫和苍蝇的寿命延长有关。开发通过控制热量限制/Rpd3/Sir2通路延长寿命的分子遗传学和药理学干预的先决条件是更好地了解该通路及其调控的基因和蛋白质。在本研究中，我们将确认Sir2在果蝇热量限制通路中的重要性，确定Sir2相对于Rpd3在该通路中的位置，确定其对长寿起重要作用的组织的时间和位置，并检查已知的增加Sir2活性的外源小分子对长寿的影响。利用我们的果蝇模型系统，我们将研究p53在延长寿命中的作用，p53是一种转录因子和肿瘤抑制因子，其活性由Sir2控制。最后，我们将使用比较微阵列分析来鉴定果蝇Rpd3/Sir2/热量限制通路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.