The Wnt-chromatin axis in aging

描述(申请人提供)：发达国家的人口存活到极端老年是人类历史上的一个显着现象。这一变化在很大程度上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，有几个相互非排他性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，该假设将这些概念中的两个-细胞衰老和表观遗传学-与以前未被认为是衰老的主要调节因子的途径联系起来，即Wnt信号。尽管没有被广泛认为是衰老的调节器，但Wnt信号通路被很好地证明是组织和生物发育以及生命后期成人组织动态平衡的进化保守的决定因素。这里提出的研究是基于两个合作实验室的最新和令人兴奋的发现。首先，Peter D.Adams(PDA)的工作表明，在体外-人成纤维细胞培养-抑制Wnt信号会触发广泛的异染色质和细胞衰老，从而表明Wnt信号参与了细胞衰老的调节。第二，John M.Sedivy(JMS)的体内研究发现，在小鼠和灵长类动物组织中，随着细胞衰老和衰老，兼性异染色质显著扩张。基于这些结果，我们认为Wnt-染色质-衰老信号轴是生物体衰老的重要决定因素。我们在这里提出了一系列实验，以启动对这个新的信号轴的研究，它的运行机制，以及它在生物衰老中的作用。Aim 1将在体外对Wnt信号减少所触发的染色质结构中与衰老相关的变化进行高分辨率的全基因组作图。目的2利用小鼠、灵长类和人类模型，研究Wnt信号、异染色质、细胞衰老和体内衰老之间的联系。目的3将评估细胞衰老和全基因组染色质的变化携带低形态的Wnt途径突变的小鼠。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，从功能上将这些与Wnt信号通路联系起来，最终为新的药物靶点开辟道路。 公共卫生相关性：老龄化是一个对社会产生深远影响的基本生物过程。衰老的一个重要方面被认为是天生难以维持的生物结构。我们的基因组被压缩成一个由DNA和蛋白质组成的复杂网络，称为染色质，很可能就是这样的结构。这项提议将对哺乳动物生物中与年龄相关的染色质修饰和重塑进行全球分析。这些发现将促进我们对衰老基本过程的理解，并可能发现药物干预以改善与年龄相关的疾病的靶点。

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.