Single Gene Mutants that Confer Longevity in Drosphila

赋予果蝇长寿的单基因突变体

• 批准号: 7919036
• 负责人: STEPHEN L HELFAND
• 金额: $ 12.52万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7919036
• 关键词: Adult; Affect; Aging-Related Process; Animals; Citric Acid Cycle; Development; Drosophila genus; Drosophila melanogaster; Future; Genes; Genetic; Goals; Homologous Gene; Human; Impairment; Intervention; Knowledge; Lead; Life; Longevity; Mammals; Messenger RNA; Metabolic; Molecular Genetics; Mutation; Nutrient; Organism; Phenotype; Physical activity; Process; Proteins; Reproduction; Research; System; Techniques; Therapeutic Intervention; Time; Tissues; Transgenes; Transgenic Organisms; dicarboxylate-binding protein; fly; gene therapy; genetic element; insight; mutant; uptake

The long-term goal of our studies is to understand the molecular and genetic elements that underlie the process of aging and determine longevity. The aim of this proposal is to understand how mutations in a single gene, Indy, result in a dramatic increase in life span in Drosophila melanogaster without a concomitant loss of reproduction, physical activity or metabolic rate. In particular we will seek to determine where and when Indy mutations act to extend life span. The function of the INDY protein as a tranporter of Krebs cycle intermediates and its preliminary localization to regions of the fly important in uptake, utilization and storage of nutrients, indicate that reductions in the level of INDY protein alters the metabolic state of the fly in a way that favors life span extension. INDY's similarity in sequence, function, and tissue expression to mammalian and human dicarboxylate transporters suggests that knowledge of how Indy mutations extend life span in flies may be useful for the development of therapeutic interventions for extending healthy life in humans. We will first examine the tissues and times during life INDY expression is altered in the long-lived Indy mutant animals. Using molecular genetic approaches we will restore Indy function to directly determine where and when Indy mutations act to extend life span. Finally we will determine which of the several possible human Indy-like genes can functionally rescue the Indy mutation. A more complete understanding of how mutations in Indy lead to life span extension should yield valuable insights into general mechanisms of life span extension relevant to a variety of organisms including humans.

我们研究的长期目标是了解构成疾病背后的分子和遗传因素。 衰老过程并决定寿命。该提案的目的是了解基因突变是如何发生的 单基因 Indy 可以在没有伴随基因的情况下显着延长果蝇的寿命 生殖能力、体力活动或代谢率的丧失。我们将特别寻求确定地点和 当印地突变发挥作用以延长寿命时。 INDY 蛋白作为克雷布斯循环转运蛋白的功能 中间体及其在果蝇吸收、利用和储存中重要区域的初步定位 营养物质，表明 INDY 蛋白水平的降低在某种程度上改变了果蝇的代谢状态 这有利于延长寿命。 INDY 在序列、功能和组织表达方面与哺乳动物相似 和人类二羧酸转运蛋白表明，了解 Indy 突变如何延长果蝇的寿命 可能有助于开发延长人类健康寿命的治疗干预措施。 我们将首先检查生命期间的组织和时间 INDY 表达在长寿的 Indy 中发生了改变 变异动物。使用分子遗传学方法，我们将恢复 Indy 功能以直接确定 Indy突变在何时何地发挥作用以延长寿命。最后我们将确定以下几个中的哪一个 可能的人类 Indy 样基因可以在功能上拯救 Indy 突变。更全面的了解 印地突变如何导致寿命延长应该为一般机制提供有价值的见解 与包括人类在内的多种生物体相关的寿命延长。