RUI: Testing the network hypothesis of Cellular Aging in Saccharomyces Cerevisiae

智力上的优点。什么是衰老？尽管进行了150多年的研究，这个问题仍然难以捉摸。在这个项目中，提出了一个新的假设，即细胞衰老是基因/蛋白质网络的一种新特性。这一假说认为，细胞衰老的可塑性，占寿命自然变化的70%~80%，主要归因于可以通过网络传播的有害变化的随机性。多态变异可以通过影响网络中相互作用的强度和动力学来改变衰老的随机过程，并可贡献寿命自然变异的20%~30%。这一假设预测，细胞老化的速度与网络的健壮性成正比，这一预测将在该项目中得到计算和实验的验证。第一个目标是检验基因对衰老的影响和它们在稳健性方面的影响之间的统计联系，并预测与衰老相关的新基因。第二个目标是通过实验测试网络健壮性和细胞老化速度之间的联系。几个网络稳健性的指标将在酵母野生分离株的集合中进行测量。然后将评估这些稳健性指标和细胞老化速率之间的关联。通过认识到细胞衰老是一种新的特性，这种新的衰老网络模型可以为其他衰老理论提供机制基础。因为细胞衰老是一种系统水平的属性，所以不能精确地定位到特定的基因。这解释了该领域的悖论，即尚未发现与衰老有直接功能联系的基因，尽管已知仅在酵母中就有80多个基因影响衰老过程。基因/蛋白质网络突现特性的一般原理也将为生物体的基因和表型之间的关系提供新的见解。该项目将有利于一所历史悠久的黑人女子学院的机构研究和教学项目。这个项目将主要由来自少数族裔背景的本科生进行。通过让这些学生参与假设驱动的研究和高强度的跨学科培训，它将培养对研究的热爱，并鼓励他们追求与科学相关的职业。该项目还将为学院的研究计划注入活力，提高研究能力。

Intellectual merit. What is aging? This question remains elusive despite over 150 years of research. In this project, the novel hypothesis is proposed that cellular aging is an emergent property of gene/protein networks. This hypothesis argues that the plasticity of cellular aging, 70~80% of natural variation in life span, is attributed mainly to the stochasticity of detrimental changes that can propagate through the networks. Polymorphic variations can alter stochastic processes of aging by influencing the strength and dynamics of interactions in the networks and can contribute to 20~30% of natural variation in life span. This hypothesis predicts that the rate of cellular aging is proportional to the robustness of the network, a prediction that will be tested in this project both computationally and experimentally. The first aim is to examine the statistical associations of the effects of genes on aging and their effects in robustness and to predict new genes associated with aging. The second aim is to test experimentally the link between network robustness and the rate of cellular aging. Several proxies of network robustness will be measured in a collection of wild isolates of yeast. The associations between these proxies of robustness and the rate of cellular aging will then be evaluated. By recognizing cellular aging as an emergent property, this novel network model of aging can provide a mechanistic foundation for other theories of aging. Because cellular aging is a system-level property, it cannot be pinpointed to specific genes. This explains the paradox in the field that not gene with a direct functional link to aging has yet to be found, even though over 80 genes are known to influence the aging process in yeast alone. The general principle of emergent properties of gene/protein networks will also offer new insights into the relationship between the genotype and phenotype of an organism.Broader impacts. The project will benefits to the institutional research and teaching programs at an historically black women's college. This project will largely be carried out by undergraduate students from a minority background. By engaging these students in hypothesis-driven research and intense interdisciplinary training, it will cultivate a love of research and encourage their pursuits of science-related careers. This project will also invigorate the research program and enhance the research capacity at this college.