The Wnt-chromatin axis in aging

描述（由申请人提供）：发达国家人口进入极端老年是人类历史上一个显著的现象。这一变化主要是通过改善公共卫生、降低儿童死亡率和减少传染病来实现的。然而，人口平均年龄的稳步增长导致诸如骨质疏松症、阿尔茨海默病、糖尿病和癌症等老年退行性疾病的负担不断增加。目前，有几个相互不排斥的模型来解释这些退行性衰老过程背后的机制。一种理论认为，细胞的复制性衰老限制了它们的增殖能力，从而限制了组织的更新。其他模型表明，随着年龄的增长，遗传和/或表观遗传（染色质）损伤的积累最终会损害细胞和组织功能。在这个应用中，我们测试了一个假设，该假设将细胞衰老和表观遗传学这两种观点与一种以前未被认为是衰老主要调节因子的途径，即Wnt信号传导联系起来。尽管不被广泛认为是衰老的调节因子，但Wnt信号通路已被充分证明是组织和生物体发育以及成年组织稳态的进化保守决定因素。这里提出的研究是基于两个合作实验室最近令人兴奋的发现。首先，Peter D. Adams （PDA）的研究表明，体外培养的人成纤维细胞中，Wnt信号的抑制会引发广泛的异染色质化和细胞衰老，从而暗示Wnt信号参与细胞衰老的调控。其次，John M. Sedivy （JMS）的体内研究发现，兼性异染色质的显著扩增与小鼠和灵长类组织的细胞衰老和衰老有关。基于这些结果，我们提出wnt -染色质-衰老信号轴是生物体衰老的重要决定因素。我们在此提出一系列的实验来启动这个新的信号轴的研究，其运作机制，以及它在机体衰老中的作用。Aim 1将对体外Wnt信号减少引发的染色质结构衰老相关变化进行高分辨率全基因组定位。目的2将研究Wnt信号、异染色质化、细胞衰老和体内衰老之间的联系，使用小鼠、灵长类动物和人类模型。目的3将评估携带亚形态Wnt通路突变的小鼠的细胞衰老和全基因组染色质变化。我们的目标是使用一种基于发现的方法来揭示衰老过程的表观基因组特征，将这些特征与Wnt信号通路功能连接起来，并最终为新的药物靶点开辟道路。

DESCRIPTION (provided by applicant): The survival of populations in developed nations into extreme old age is a remarkable phenomenon in human history. This change has come about largely through improved public hygiene, decreased child mortality and a decrease in infectious diseases. However, the steady increases in the average age of the population have resulted in an ever increasing burden of the degenerative diseases of aging, such as osteoporosis, Alzheimer's disease, diabetes and cancer. Currently, there are several mutually non-exclusive models to explain the mechanisms behind these degenerative aging processes. One theory is centered on the idea that replicative senescence of cells limits their proliferative capacity and hence tissue renewal. Other models suggest that accumulation of genetic and/or epigenetic (chromatin) damage with age eventually impairs cell and tissue function. In this application, we test a hypothesis that links two of these ideas - cellular senescence and epigenetics - to a pathway that has not previously been considered to be a major regulator of aging, namely, Wnt signaling. Although not widely viewed as a regulator of aging, the Wnt signaling pathway is well documented to be an evolutionarily conserved determinant of tissue and organismal development, and later in life, adult tissue homeostasis. The research proposed here is based on recent and exciting discoveries in the two collaborating laboratories. First, the work of Peter D. Adams (PDA) has implicated Wnt signaling in the regulation of cellular senescence by showing that in vitro - human fibroblast cell culture - repression of Wnt signaling triggers extensive heterochromatinization and cellular senescence. Second, the in vivo studies of John M. Sedivy (JMS) have found that a marked expansion of facultative heterochromatin occurs in association with cellular senescence and aging in mouse and primate tissues. Based on these results we propose that a Wnt-Chromatin-Senescence signaling axis is an important determinant of organismal aging. We propose here a series of experiments to initiate the investigation of this novel signaling axis, the mechanisms of its operation, and its role in organismal aging. Aim 1 will perform high resolution, genome-wide mapping of senescence-associated changes in chromatin structure that are triggered by reduced Wnt signaling in vitro. Aim 2 will investigate the links between Wnt signaling, heterochromatinization, cellular senescence and aging in vivo, using mouse, primate and human models. Aim 3 will assess cellular senescence and genome- wide chromatin changes in mice harboring hypomorphic Wnt pathway mutations. Our goal is to use a discovery-based approach to reveal epigenome-wide characteristics of aging processes, functionally connect these with Wnt signaling pathways, and ultimately open the road to new pharmaceutical targets. PUBLIC HEALTH RELEVANCE: Aging is a fundamental biological process with a profound impact on society. An important aspect of aging is believed to be biological structures that are inherently difficult to maintain. Our genomes, which are compacted into a complex network of DNA and protein referred to as chromatin, are likely to be one such structure. This proposal will perform a global analysis of age-associated chromatin modifications and remodelling in mammalian organisms. These discoveries will advance our understanding of the basic processes of aging, as well as potentially uncover targets for pharmaceutical intervention to ameliorate age-related disorders.