Cell Senescence, Carcinogenesis, and Aging

细胞衰老、癌变和衰老

• 批准号: 7053948
• 负责人: james barrett
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7053948
• 关键词: DNA damage; aging; amidohydrolases; biological signal transduction; caloric dietary content; cancer risk; carcinogenesis; cell senescence; disease /disorder model; enzyme activity; enzyme mechanism; gene expression; human genetic material tag; hypoxia; molecular cloning; obesity; oxidative stress; protein localization; protein structure function; telomerase; tissue /cell culture; tumor suppressor genes

Aging is a major risk factor of human cancers. Our project is to elucidate molecular mechanisms of aging and cancer using cellular and animal models. We have shown that normal human cells have telomerase-dependent and independent pathways for cellular senescence, which both serve as a tumor suppressive mechanism. The senescence genes on chromosome 3p21 (a transcriptional repressor of the telomerase hTERT gene) and chromosome 1q42.3 (which functions independently of telomerase regulation) are to be cloned by the positional and functional cloning methods. To understand a link between cellular aging and organismal aging, we study SIRTs, human homologs of the yeast/worm longevity gene Sir-2 encoding a NAD-dependent protein deacetylase. Our data suggest the more complex regulation of aging processes in humans than in yeast or worms and multiple functions of human SIRT proteins at different cellular locations (i.e., nucleus, nucleolus, cytoplasm and mitochondria). We have found that DNA double-strand breaks (DSB) accumulate in mammalian cells during both cellular senescence and in vivo aging, providing important insight into the mechanism by which cellular senescence contribute to organismal aging. We are also examining how various local or systemic conditions (e.g., hypoxia, oxidative stress, obesity, calorie intake) affect the above-mentioned pathways/factors to regulate human aging and carcinogenesis processes.

衰老是人类癌症的主要风险因素。我们的项目是利用细胞和动物模型阐明衰老和癌症的分子机制。我们已经证明，正常人类细胞有端粒酶依赖和独立的细胞衰老途径，这两种途径都是一种肿瘤抑制机制。染色体3p21(端粒酶hTERT基因转录抑制因子)和1q42.3(不受端粒酶调控)上的衰老基因将通过定位克隆和功能克隆的方法进行克隆。为了了解细胞衰老和生物衰老之间的联系，我们研究了SIRT，这是酵母/蠕虫长寿基因SIR-2的人类同源物，编码一种依赖于NAD的蛋白质去乙酰基酶。我们的数据表明，人类衰老过程的调控比酵母或蠕虫更复杂，人类SIRT蛋白在不同细胞位置(即核、核仁、细胞质和线粒体)具有多种功能。我们发现，DNA双链断裂(DSB)在细胞衰老和体内衰老过程中都会在哺乳动物细胞中积累，这为了解细胞衰老促进生物衰老的机制提供了重要的见解。我们也在研究各种局部或全身情况(如缺氧、氧化应激、肥胖、卡路里摄入)如何影响上述调节人类衰老和致癌过程的途径/因素。