Mechanisms of Longevity Regulation in Yeast

描述（由申请人提供）：在简单模式生物中调节寿命的基因和途径的鉴定对于初步了解哺乳动物衰老机制具有不可估量的价值。本申请中提出的系统生物学和遗传学研究将有助于确定各种信号转导基因和途径在单细胞真核生物酿酒酵母衰老调控和抵抗各种应激损伤中的作用。这些途径以Ras和Sch9蛋白为中心，这些蛋白从酵母到人类都是保守的，与癌症和其他疾病有关。建议的研究将：1)阐明先前发现的促衰老基因（包括RAS2和SCH9）作用的基本分子机制；2)研究影响衰老和抗损伤的新分子、基因和途径，这些可能从酵母到人类都保守；3)开发一种新的研究衰老的范式，这种范式更简单，更直接地与哺乳动物的衰老相关。4)研究卡路里限制的抗衰老分子机制，这种机制似乎从酵母到哺乳动物都是保守的。拟议的研究将有助于描述衰老的基本机制，也有助于确定可以预防人类疾病的新基因和途径。公共卫生相关性：历史上，包括面包酵母、线虫和苍蝇在内的简单模型系统已经产生了大量的发现，为理解和治疗人类疾病提供了基础。本应用程序中提出的研究旨在了解类似于人类基因Ras和Akt的酵母基因如何影响衰老和保护细胞免受损伤。了解这些基因如何调节酵母和其他简单系统中的衰老，将加速识别可被调节以防止人类疾病的基因和途径（Longo和Finch， 2003）。例如，导致Akt或Ras激活的突变会加速酵母的衰老，但在大部分人类癌症中也发现了这种突变。

DESCRIPTION (provided by applicant): The identification of the genes and pathways that regulate the life span in simple model organisms has been invaluable to the initial understanding of the mechanisms of aging in mammals. The systems biology and genetic studies proposed in this application will help define the role of various signal transduction genes and pathways in the regulation of aging and resistance to the damage caused by various stresses in the unicellular eukaryote S. cerevisiae. These pathways are centered around the Ras and Sch9 proteins, which are conserved from yeast to humans, and are implicated in cancer and other diseases. The proposed studies will: 1) shed light on the fundamental molecular mechanisms responsible for the effects of previously identified pro-aging genes including RAS2 and SCH9, 2) investigate novel molecules, genes, and pathways that affect aging and resistance to damage and that may be conserved from yeast to humans, 3) develop a novel paradigm to study aging, that is simpler and more directly relevant to aging in mammals, 4) investigate the anti-aging molecular mechanisms of calorie restriction which appear to be conserved from yeast to mammals. The proposed studies will contribute to the description of the fundamental mechanisms of aging and also to the identification of novel genes and pathways that can protect against human diseases. Public Health Relevance: Historically, simple model systems including baker's yeast, nematodes, and flies have yielded a remarkable number of discoveries that have provided the foundation for the understanding and treatment of human diseases. The studies proposed in this application are aimed at understanding how yeast genes that are analogous to the human genes Ras and Akt affect aging and the protection of cells against damage. The understanding of how these genes regulate aging in yeast and other simple systems will accelerate the identification of genes and pathways that can be modulated to protect against diseases in humans (Longo and Finch, 2003). For example, mutations that cause activation of Akt or Ras accelerate aging in yeast but are also found in a major portion of human cancers.