The Role of Enhancer of Zeste Homolog 2 in Cellular Senescence

描述(申请人提供)：年龄是许多疾病的主要危险因素，包括癌症、心血管疾病、神经退行性变和II型糖尿病。最近的研究已经确定了决定和调节生物衰老并影响所有器官系统的普遍机制。了解衰老的基本过程有望为延缓许多与年龄相关的疾病的发生提供治疗目标。新出现的证据表明，细胞衰老参与了生物体衰老的生理过程。细胞衰老是指由端粒缩短和各种细胞压力引起的不可逆转的生长停滞。Zust Homolog 2的多梳蛋白增强子(EZH2)是一种甲基转移酶，催化组蛋白3赖氨酸27位的三甲基化(H3K27me3)，参与调节细胞衰老。我研究的长期目标是了解导致衰老的分子过程。具体地说，我在这里提出了一系列机制实验和全基因组分析来研究EZH2调节细胞衰老的机制。目标1将使用敲除和过度表达策略来研究EZH2和Wnt信号通路之间的联系，Wnt信号通路是一种已知的细胞衰老调节因子。目的2将研究EZH2的抑制触发活性氧物种增加的机制。目的3将研究在衰老过程中由EZH2下调引起的全球染色质结构的变化。我的研究将有助于确定表观遗传变化影响和调节细胞衰老的新机制。这一知识预计将为干预措施开辟新的途径，以延缓与年龄相关的疾病，并增加人类的健康寿命。

DESCRIPTION (provided by applicant): Age is a major risk factor for many diseases including cancer, cardiovascular disease, neurodegeneration, and type II diabetes. Recent research has identified universal mechanisms that determine and regulate organismal aging, and impact all organ systems. Understanding the fundamental processes of aging is expected to provide therapeutic targets to delay the onset of many age-associated diseases. Emerging evidence suggests that cellular senescence contributes to the physiological process of organismal aging. Cellular senescence refers to the irreversible growth arrest that is triggered by telomere shortening and also by a variety of cellular stresses. The Polycomb group protein Enhancer of Zeste Homolog 2 (EZH2), a methyltransferase that catalyzes the tri-methylation of histone 3 at lysine 27 (H3K27me3), has been implicated in regulating cellular senescence. The long-term objective of my research is to understand the molecular processes that contribute to senescence. Specifically, I propose here a series of mechanistic experiments and genome-wide analyses to investigate the mechanisms by which EZH2 regulates cellular senescence. Aim 1 will examine the connections between EZH2 and the Wnt signaling pathway, a known regulator of cellular senescence, using knockdown and overexpression strategies. Aim 2 will investigate the mechanism by which repression of EZH2 triggers the increase in reactive oxygen species. Aim 3 will examine the changes in global chromatin structure that are triggered during senescence induced by the downregulation of EZH2. My studies will help define novel mechanisms by which epigenetic changes impact and regulate cellular senescence. This knowledge is expected to open new avenues for interventions to delay age-associated diseases and increase human health span.