Effectors of cellular senescence states

细胞衰老状态的效应器

• 批准号: 8278573
• 负责人: John M Sedivy
• 金额: $ 31.6万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8278573
• 关键词: Address; Age; Aging; Area; Belief; Biological; Biological Assay; Biological Markers; Biological Models; Caloric Restriction; Cell Aging; Cell Culture Techniques; Cell division; Cells; Chromatin; Chromatin Structure; Collaborations; Collection; Cyclin-Dependent Kinase Inhibitor 2A; DNA; DNA Damage; Data; Detection; Drug or chemical Tissue Distribution; Elderly; Epigenetic Process; Evaluation; Event; Evolution; Functional disorder; Generations; Goals; Growth; Health; Heterochromatin; Human; Individual; Knowledge; Lead; Life; Link; Longevity; Macaca mulatta; Malignant Neoplasms; Measures; Memory; Methods; Microscopic; Modeling; Monitor; Mus; Normal Cell; Normal tissue morphology; Nutrient; Oncogenes; Organism; Oxidative Stress; Papio; Pathology; Pathway interactions; Polycomb; Primates; Process; Reactive Oxygen Species; Relaxation; Rodent; Role; Signal Pathway; Sirtuins; Site; Stem cells; Stimulus; Stress; Telomere Shortening; Tissues; Tumor Suppression; Tumor Suppressor Proteins; Up-Regulation; Work; age related; base; cell age; cell type; chromatin modification; cohort; exhaustion; foot; genome-wide; in vivo; in vivo Model; insulin signaling; mouse model; pleiotropism; reproductive; research study; response; retinoblastoma tumor suppressor; senescence; telomere; trait; tumor; ultraviolet irradiation

DESCRIPTION (provided by applicant): Replicative cellular senescence is a phenomenon of irreversible growth arrest triggered by the accumulation of a discrete number of cell divisions. The great majority of normal cell types from all vertebrate species examined display this response. It is becoming increasingly evident that what has classically been described as cellular senescence is a collection of interrelated states that can be triggered by distinct intrinsic and extrinsic stimuli. The underlying cause of senescence due to replicative exhaustion is telomere shortening. In addition, it is now apparent that many types of stress, reactive oxygen species, pharmacological agents, and even nutrient imbalances can trigger a senescence response. Activation of some oncogenes also induces senescence in normal cells, and recent data have implicated cellular senescence as an important in vivo tumor suppression mechanism. In contrast, the connections between cellular senescence and the aging of organisms are significantly more tenuous. The necessary first step is to distinguish senescent cells from the majority of healthy but quiescent cells found in normal tissues. We, and others, have recently developed a method based on the microscopic detection of DNA damage markers localized to telomeres, designated the `TIF' assay (for `telomere dysfunction-induced foci'). TIFs are a robust biomarker of telomere-initiated senescence, which we used to demonstrate a marked age-associated accumulation of senescent cells in normal primate tissues. This proposal is aimed to give us a better understanding of multiple cellular senescence processes, focusing on their roles in organismal aging. Aim 1 will examine the in vivo occurrence of telomere-induced senescence in mouse, primate and human models, and probe the links between cellular senescence and pathways that functionally influence aging. Aim 2 will extend recent studies linking genome-wide changes in chromatin structure with cellular senescence by developing new assays to assess in vivo states of heterochromatin in cells and tissues. These new biomarkers of cellular senescence will then be applied to the models developed in Aim 1. Aim 3 will seek to discover what causes the age-dependent upregulation of the cyclin-dependent kinase inhibitor p16, an important effector implicated in regulating multiple senescent states. PUBLIC HEALTH RELEVANCE: Replicative cellular senescence was discovered and first described as an irreversible growth arrest triggered by the accumulation of a discrete number of cell divisions. These findings generated two hypotheses regarding the significance of cellular senescence: that it contributes to aging, and that it suppresses cancer. Recent data have implicated cellular senescence as an important in vivo tumor suppression mechanism in a variety of human and mouse tissues. In contrast to tumor suppression, the connections between cellular senescence and the aging of organisms are significantly more tenuous. The necessary first step is to distinguish senescent cells from the majority of healthy but quiescent cells found in normal tissues. This proposal will develop new biomarkers of cellular senescence that will be applied in vivo investigate the occurrence of senescent cells in rodents, primates and humans. Mechanisms that lead to the generation of senescent cells will also be investigated, as well as the persistence of senescent cells.

描述（由申请人提供）：复制性细胞衰老是由离散数量的细胞分裂累积引发的不可逆生长停滞的现象。所有检查的脊椎动物物种的普通细胞类型绝大多数都显示出此反应。越来越明显的是，经典被描述为细胞衰老是相互关联的状态的集合，可以由独特的内在刺激和外在刺激触发。复制疲劳引起的衰老的根本原因是端粒缩短。此外，现在很明显，许多类型的压力，活性氧，药理学剂甚至营养失衡都会触发衰老反应。某些癌基因的激活还会诱导正常细胞的衰老，并且最近的数据将细胞衰老视为体内肿瘤抑制机制的重要性。相比之下，细胞衰老与生物体衰老之间的联系明显更脆弱。必要的第一步是将衰变细胞与正常组织中发现的大多数健康但静止的细胞区分开。我们和其他人最近开发了一种基于定位于端粒的DNA损伤标记的显微镜检测的方法，该标志物指定了“ TIF”测定法（用于“端粒功能障碍诱导的灶”）。 TIF是端粒引起的衰老的强大生物标志物，我们用来证明在正常灵长类动物组织中衰老细胞显着相关的衰老积累。该建议的目的是使我们更好地了解多个细胞衰老过程，重点是它们在有机体衰老中的作用。 AIM 1将检查小鼠，灵长类动物和人类模型中端粒诱导的衰老的体内发生，并探测细胞衰老与功能影响衰老的途径之间的联系。 AIM 2将扩展最新的研究，将染色质结构的全基因组变化与细胞衰老联系起来，通过开发新测定，以评估细胞和组织中异染色质的体内状态。然后，这些新的细胞衰老生物标志物将应用于AIM 1中开发的模型。AIM3将寻求发现导致细胞周期蛋白依赖性激酶抑制剂p16的年龄依赖性上调的是什么，这是一种与调节多个衰老状态有关的重要效应。公共卫生相关性：发现了复制性细胞衰老，并首先被描述为不可逆的生长停滞，这是由于分散数量的细胞分裂的积累而引起的。这些发现对细胞衰老的重要性产生了两个假设：它有助于衰老，并抑制癌症。最近的数据表明，细胞衰老是多种人和小鼠组织中体内抑制机制的重要重要性。与肿瘤抑制相反，细胞衰老与生物体衰老之间的连接明显更脆弱。必要的第一步是将衰变细胞与正常组织中发现的大多数健康但静止的细胞区分开。该建议将开发出新的细胞衰老生物标志物，并将在体内应用，研究啮齿动物，灵长类动物和人类中衰老细胞的发生。还将研究导致衰老细胞产生的机制，以及衰老细胞的持续性。