Network-Driven Dynamics of Replicative Aging

项目摘要 细胞衰老是一个复杂的生物学过程，与许多疾病有关，如癌症， 糖尿病和神经退行性疾病。减缓衰老的新治疗方法有望 减少全球慢性病的医疗负担。然而，这些方法的发展 需要深入了解衰老的机制，这仍然是一个具有挑战性的目标。静态 基于人群的研究不足以揭示衰老背后复杂的分子机制， 这是因为遗传上相同的细胞有各种内在的衰老原因， 衰老此外，尽管许多单个基因对寿命有深远的影响，但它们如何相互作用， 在基因调控网络中发挥作用，调节衰老，以及这些相互作用如何动态变化 在很大程度上仍然未知。为了克服这些挑战，我们开发了高通量 微流控技术，以跟踪整个复制生命周期的分子过程的动态， 单个酿酒酵母细胞。在拟议的研究中，这些动态测量技术将 与计算建模相结合，系统地描述和量化集体动态 衰老相关分子网络的行为。在目标1中，我们将定量表征 与细胞衰老的不同原因相关的变化，并基于这些数据，构建了一个现象学 衰老过程的模型，在此基础上，我们将建立保守的Sir 2和蛋白质的机制模型 激酶A（PKA）调节的分子网络，两者都与衰老密切相关。特别是 目标2，我们将开发一个Sir 2调控的分子网络的机制模型，以预测其动力学， 在衰老过程中的调节作用。将进行高通量单细胞分析，以跟踪 Sir 2调节的基因，并测试模型预测。在目标3中，我们将系统地描述PKA- 调节老化过程中的应激反应，并建立一个机制模型，以量化和预测的影响， 衰老的环境线索我们将系统地研究压力反应的动力学和贡献 基因在各种环境干扰下的变化。这些实验测量将用于测试 预测，完善模型，更重要的是，提供洞察的基本机制， 老化的环境控制。为了实现这些目标，我们组建了一支强大的跨学科团队 具有互补专业知识的调查人员，他们将协同工作， 从系统生物学的角度来研究衰老的生物学。 !

Project Summary Cellular aging is a complex biological process, associated with many diseases, such as cancer, diabetes, and neurodegenerative diseases. New therapeutic approaches to slow aging hold promise for reducing global healthcare burdens of chronic diseases. However, the development of these approaches requires a deep understanding of the mechanisms of aging, which remains a challenging goal. Static population-based studies are insufficient to reveal sophisticated molecular mechanisms that underlie the aging process, because genetically identical cells have various intrinsic causes of aging and widely different rates of aging. Furthermore, although many single genes have profound effects on lifespan, how they interact and function within gene regulatory networks to regulate aging and how these interactions change dynamically during aging remain largely unknown. To overcome these challenges, we have developed high-throughput microfluidic technologies to track the dynamics of molecular processes throughout the replicative lifespans of single S.cerevisiae cells. In the proposed research, these dynamic measurement technologies will be integrated with computational modeling to systematically characterize and quantify the collective dynamic behaviors of aging-related molecular networks. In Aim 1, we will quantitatively characterize the phenotypic changes associated with distinct causes of cell aging and, based on these data, construct a phenomenological model of the aging process, upon which we will build mechanistic models of the conserved Sir2 and protein kinase A (PKA)-regulated molecular networks, both of which are deeply connected to aging. In particular, in Aim 2, we will develop a mechanistic model of the Sir2-regulated molecular network to predict its dynamics and regulatory roles during aging. High-throughout single-cell analysis will be performed to track the dynamics of Sir2-regulated genes and test the model predictions. In Aim 3, we will systematically characterize the PKA- regulated stress response during aging and develop a mechanistic model to quantify and predict the effects of environmental cues on aging. We will systematically examine the dynamics and contribution of stress response genes under various environmental perturbations. These experimental measurements will be used to test the predictions, refine the model, and more importantly, provide insight into the basic mechanisms underlying the environmental control of aging. To accomplish these aims, we have assembled a strong interdisciplinary team of investigators with complementary expertise, who will work synergistically to tackle fundamental questions in the biology of aging from a systems biology perspective. !