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

线虫 Sir-2 基因与衰老的分子研究

• 批准号: 8039925
• 负责人: LEONARD P GUARENTE
• 金额: $ 28.66万
• 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 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8039925
• 关键词: Aging; Animal Model; Applications Grants; Area; Automobile Driving; Biological; Caenorhabditis elegans; Caloric Restriction; Cell physiology; Cells; Diet; Disease; Foundations; Genes; Genetic; Grant; Head; Health; Health Benefit; Hormonal; Hormones; Human; Intervention; Knowledge; Lead; Link; Longevity; Mammals; Mediating; Mitochondria; Modeling; Molecular; Molecular Genetics; Nematoda; Neurons; Organism; Outcome Study; Pathway interactions; Physiological; Physiology; Process; Proteins; Regimen; Research; Respiration; Rodent Model; Role; Sirtuins; System; Work; aging population; dietary restriction; improved; lipid metabolism; novel therapeutic intervention; public health relevance; response; tool

DESCRIPTION (provided by applicant): The work described in this grant application will bring about fundamental knowledge in two important areas of current aging research. The first is calorie restriction (CR), which is a dietary regimen known to provide broad health benefits and longevity. The second is SIR2 and its related proteins (sirtuins), which have emerged in the past five years as important regulators of aging in a broad spectrum of model organisms. Studies in the prior period have begun to identify pathways by which CR operates in C. elegans. The first two aims in this grant will focus in on these pathway and identify hormones and cellular processes that are critical for CR to extend the lifespan of worms. We have pinpointed two neurons in the head that trigger broad physiological changes in response to CR, such as an increase in respiration, and we will figure out what hormonal factor these cells release to bring about the observed changes leading to long lifespan. In the third aim, we will study in detail the four sirtuin genes in C. elegans. Since sirtuins have been linked to CR in other organisms, we will investigate whether this is true in worms, which sirtuins are involved, and how they bring about their effects. The C. elegans system we have set up to study CR offers many advantages, including all of the genetic and molecular tools that have solved many other important biological problems in the nematode model. CR itself has salutary effects against many of the major diseases of aging in rodent models. It is possible that a molecular understanding of CR will allow us to tap genetic pathways to provide broad health benefits for our aging population. This approach is complementary to the current focus on the molecular details of particular diseases to develop specific therapies. Beyond this important practical outcome, this study will provide important new information on the sirtuins and pathways that relate diet to physiology. There is an excellent foundation to build on in the next granting period and important findings are anticipated. Public Health relevance: Dietary restriction is the most robust intervention that extends life span and improves health in mammals. This project details a study of dietary restriction in the roundworm C. elegans that will identify new genes, mechanisms and pathways driving this process. Our findings may lead to new therapeutic approaches to diseases of aging in humans.

描述（由申请人提供）：本赠款申请中描述的工作将在当前老龄化研究的两个重要领域带来基本知识。首先是卡路里限制（CR），这是一种饮食方案，已知可提供广泛的健康益处和寿命。第二个是SIR2及其相关蛋白（SIRTUINS），它们在过去五年中作为重要的模型生物中的重要调节剂出现。上一个时期的研究已经开始鉴定CR在秀丽隐杆线虫中运行的途径。该赠款中的前两个目标将重点放在这些途径上，并确定CR延长蠕虫寿命至关重要的激素和细胞过程。我们已经指出了两个神经元的头部神经元，这些神经元触发了响应CR的广泛生理变化，例如呼吸的增加，我们将弄清楚这些细胞释放的激素因子是什么，从而导致观察到的变化导致长寿。在第三个目标中，我们将详细研究秀丽隐杆线虫中的四个Sirtuin基因。由于Sirtuins已与其他生物中的CR相关，因此我们将研究在蠕虫中是否正确，涉及Sirtuins以及它们如何产生其效果。我们为研究CR设立的秀丽隐杆线虫系统提供了许多优势，包括所有解决线虫模型中许多其他重要生物学问题的遗传和分子工具。 CR本身对啮齿动物模型中许多主要衰老的主要疾病具有有益的影响。对CR的分子理解可能会使我们能够利用遗传途径为我们的老龄化人群提供广泛的健康益处。这种方法与当前对特定疾病的分子细节的重点互补，以开发特定的疗法。除了这一重要的实际结果外，这项研究还将提供有关将饮食与生理学相关的Sirtuins和途径的重要新信息。在下一个授予期间，有一个绝佳的基础，可以预期重要的发现。 公共卫生相关性：饮食限制是延长寿命并改善哺乳动物健康的最强大干预措施。该项目详细介绍了一项对round虫秀丽隐杆线虫中饮食限制的研究，该研究将确定推动这一过程的新基因，机制和途径。我们的发现可能会导致新的治疗方法来治疗人类衰老的疾病。