Molecular Study of sir-2 genes and Aging in C. elegans

Sir-2 基因与秀丽隐杆线虫衰老的分子研究

• 批准号: 6508833
• 负责人: LEONARD P GUARENTE
• 金额: $ 31.64万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6508833
• 关键词: Caenorhabditis elegans; Escherichia coli; amidohydrolases; antisense nucleic acid; antiserum; biological signal transduction; caloric dietary content; chromatin; developmental genetics; dietary control; double stranded RNA; gene expression; genetic regulation; genetically modified animals; immunoprecipitation; insulin; laboratory rabbit; longevity; nicotinamide adenine dinucleotide; nutrition of aging; nutrition related tag; protein structure function

DESCRIPTION (provided by applicant): Aging has been shown to be under genetic control in model organisms. One of the genes that determines longevity in yeast and C. elegans (roundworms) is SIR2. The greater the activity of SIR2, the longer the life span in these organisms. The biochemical activity of Sir2 protein is that of an NAD-dependent histone deacetylase. A major challenge now is to determine how this activity might determine life span and whether the longevity dictated by SIR2 is subject to physiological regulation. One established physiological regimen that has been shown to extend life span is calorie restriction (CR). Limiting the calories in the diet extends the life spans of rodents, fruit flies, worms, and yeast. The mechanism by which CR extends life span is not clear. In yeast the extension induced by CR requires SIR2, implying that Sir2 protein and NAD are involved in the mechanism. In this proposal we will establish a petri plate-based replica of CR in worms and test the possible involvement of the sir-2 genes of this animal in the response to CR. Further, we will probe by genetic and molecular approaches how the sir-2.1 gene of C. elegans extends life span in this animal by regulating the known pathway of insulin signaling in worms. These studies ought to pinpoint the roles that the four sir genes play in the determination of life span in C. elegans. They also may shed light on a molecular mechanism of CR in an animal. These findings may have direct relevance to aging and the extension of life span by CR in mammals.

描述（由申请人提供）：在模型生物体中，衰老已显示在遗传控制下。确定酵母中寿命和秀丽隐杆线虫（round虫）寿命的基因之一是Sir2。 SIR2的活性越大，这些生物的寿命越长。 SIR2蛋白的生化活性是NAD依赖性组蛋白脱乙酰基酶的生化活性。现在的一个主要挑战是确定这种活动可能如何确定寿命以及SIR2决定的寿命是否受生理调节的约束。一种已证明可以延长寿命跨度的已建立的生理方案是卡路里限制（CR）。限制饮食中的卡路里扩大了啮齿动物，果蝇，蠕虫和酵母的寿命。 CR延长寿命的机制尚不清楚。在酵母中，由Cr诱导的延伸需要SIR2，这意味着Sir2蛋白和NAD参与了该机理。在此提案中，我们将在蠕虫中建立基于培养皿的Cr的复制品，并测试该动物对CR反应的SIR-2基因的可能参与。此外，我们将通过遗传和分子方法探测秀丽隐杆线虫的SIR-2.1基因如何通过调节蠕虫中胰岛素信号的已知途径来延长该动物的寿命。这些研究应该指出四个Sir基因在确定秀丽隐杆线虫生命跨度中所起的作用。他们还可以阐明动物中CR的分子机制。这些发现可能与哺乳动物中CR的衰老和寿命延长有关。