Epigenetics of Aging and Age-associated Diseases

描述(申请人提供)：表观遗传学被定义为基因组功能和表型的可遗传变化，不涉及DNA序列的改变。这种对基因组功能的更高水平的控制体现在染色质中，染色质是核小体(DNA和组蛋白)以及其他非组蛋白的复合体。人类疾病越来越多地与表观遗传学和染色质变化联系在一起。这个计划项目的中心假设是，染色质作为一种固有的动态结构，容易发生与年龄相关的退化，但这种退化也被保护过程所抵消。该计划项目研究这些与年龄相关的Chcomatin变化，因为它们发生在细胞衰老的背景下，细胞衰老是损伤细胞的不可逆转的增殖停滞，导致组织老化。我们从第一个资助周期开始的研究证实了之前怀疑的表观遗传学作为衰老和长寿的关键决定因素的作用。作为一个跨学科和高度协作的团队(到目前为止，在2008-2013年的资金周期中有46篇手稿[发表或提交]，其中19篇是合作的)，我们将继续在酵母和人类细胞中使用生物化学、结构生物学、细胞生物学、YAS遗传学和最先进的表观基因组学技术，以阐明表观遗传学在衰老和衰老中的作用。特别是，我们将定义染色质的退行性和保护性变化，以及它们背后的分子机制。这些研究与衰老的相关性将通过参照年轻的和老年的人类组织以及在小鼠模型中进行检验，评估衰老的表型。此外，基于我们在第一轮融资中的发现，我们已经开始努力利用我们对先导化合物的机械洞察力来开发新的疗法，以促进健康老龄化。我们的最终目标是了解最终导致与年龄相关的染色质功能障碍的过程的平衡，以便我们能够设计策略来操纵这种平衡以促进健康的衰老。

DESCRIPTION (provided by applicant): Epigenetics is defined as heritable changes in genomic function and phenotype that do not involve alteration to DNA sequence. This higher level control of genome function is embodied in chromatin, a composite of nucleosomes (DNA and histones), as well as other non-histone proteins. Human disease is increasingly being linked to epigenetic and chromatin changes. The central hypothesis of this Program Project is that chromatin, as an inherently dynamic structure, is prone to age-associated degeneration, but that this degeneration is also countered by protective processes. This Program Project studies these age-associated chcomatin changes as they occur in the context of cell senescence, an irreversible proliferation arrest of damaged cells that contributes to tissue aging. Our studies from the first cycle of funding confirmed the previously suspected role for epigenetics as a critical determinant of aging and longevity. As a cross-disciplinary and highly collaborative team (46 manuscripts to date [published or submitted] in the 2008-2013 funding cycle, of which 19 are collaborative), we will continue to employ biochemistry, structural biology, cell biology, yeas genetics, and state-of-the-art epigenomic technologies in yeast and human cells to elucidate the role of epigenetics in aging and senescence. In particular, we will define degenerative and protective changes to chromatin, and the molecular mechanisms underlying them. The relevance of these studies for aging will be tested by reference to young and old human tissues and in mouse models, assessing phenotypes of aging. Moreover, based on our findings from the first cycle of funding, we have already initiated efforts to leverage our mechanistic insights into lead compounds for novel therapies to promote healthy aging. Our ultimate goal is to understand the balance of processes that culminate in age-associated chromatin dysfunction, so that we can devise strategies to manipulate the balance to promote healthy aging.