Single Gene Mutants that Confer Longevity in Drosphila

我们研究的长期目标是了解这些疾病背后的分子和遗传因素。 衰老过程并决定寿命。这项提案的目的是了解突变如何在一个 单个基因Indy导致黑腹果蝇寿命显著增加，而没有伴随的 丧失生殖能力、体力活动或代谢率。特别是，我们将努力确定在哪里， 基因突变可以延长寿命INDY蛋白作为Krebs循环转运蛋白的功能 中间体及其在果蝇摄取、利用和储存重要区域的初步定位 表明INDY蛋白质水平的降低在某种程度上改变了果蝇的代谢状态 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，关于Indy突变如何延长苍蝇寿命的知识 可用于开发延长人类健康寿命的治疗干预。 我们将首先检查组织和时间在生活中INDY表达是改变在长寿的Indy 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突变在何时何地起作用以延长寿命。最后，我们将决定哪几个 可能的人类Indy样基因可以在功能上拯救Indy突变。的更完整的理解 Indy基因突变如何导致寿命延长的研究应该会对一般机制产生有价值的见解 寿命延长的理论与包括人类在内的各种生物有关。

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.