Telomere Induced Genomic Instability in Premature Aging

端粒诱导的过早衰老基因组不稳定

• 批准号: 6903410
• 负责人: Sandy S Chang
• 金额: $ 20.8万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6903410
• 关键词: DNA damage; Werner' s syndrome; apoptosis; carcinogenesis; cell cycle; cell line; cell proliferation; cytogenetics; developmental genetics; disease /disorder model; genetic models; genetically modified animals; glucose tolerance; glucose tolerance test; insulin; laboratory mouse; neoplasm /cancer genetics; osteoporosis; phenotype; premature aging; stem cells; telomere; wound healing

DESCRIPTION (provided by applicant): Genetic studies of human progeric syndromes have furthered our understanding of the molecular mechanisms of the aging process. Mutations in Wrn causes Wemer Syndrome (WS), a disease characterized by premature aging, elevated genomic instability and cancer. WS fibroblasts prematurely senescence due to telomere shortening, suggesting the possibility that telomere dysfunction collaborates with Wrn loss to generate WS. Telomeres function to prevent chromosomal ends from being recognized as double-strand DNA breaks and confer genome stability. It has been postulated that telomere shortening serves as a molecular clock that eventually signals replicative senescence. WS cells senescence while still possessing long telomeres, suggesting that they may be hypersensitive to telomere shortening. This hypothesis is supported by the observation that the senescence phenotype observed in WS cells can be rescued by overexpression of telomerase, suggesting that one consequence of the WS defect is the acceleration of normal telomere-based senescence. Mice lacking WRN do not display obvious aging phenotypes, and I hypothesize that manifestation of the WS phenotype requires the presence of critically short telomeres. Mouse telomeres are normally too long for the required telomere attrition to take place during the aging process. To test experimentally the hypothesis that manifestation of the WS phenotype in WRN-/- mice requires critical telomere shortening, telomere lengths were shortened genetically via successive intercrossings of WRN-/- mTERC-/- mice. Compound mutant mice with short dysfunctional telomeres exhibited early onset of aging phenotypes, including alopecia, cataract formation and glucose intolerance and died prematurely. These exciting results suggest that our mouse model recapitulates features of WS observed in human patients. Our immediate goal is to characterize additional aging phenotypes in these mice and to correlate the onset of premature aging with genomic instability induced by telomere dysfunction. We are also probing for molecular mechanisms that may be responsible for the observed aging phenotypes in our mouse model. These studies should illuminate the roles of Wrn and dysfunctional telomeres during human aging.

描述（由申请人提供）：人类进程综合征的遗传研究进一步了解了我们对衰老过程的分子机制的理解。 WRN突变引起Wemer综合征（WS），该疾病以过早衰老，基因组不稳定性和癌症的升高为特征。 WS成纤维细胞由于端粒缩短而过早衰老，这表明端粒功能障碍与WRN损失合作产生WS的可能性。端粒功能可防止染色体末端被识别为双链DNA断裂并赋予基因组稳定性。据推测，端粒缩短是一个分子时钟，最终向复制衰老发出信号。 WS细胞衰老，同时仍具有较长的端粒，表明它们可能对端粒缩短过敏。这一假设得到了以下观察结果：在WS细胞中观察到的衰老表型可以通过端粒酶过表达来挽救，这表明WS缺陷的结果是基于正常端粒衰老的加速。缺乏WRN的小鼠没有显示明显的衰老表型，我假设WS表型的表现需要存在严重的短端粒。小鼠端粒通常太长了，无法在老化过程中进行所需的端粒损耗。 为了通过实验测试WR-/ - 小鼠中WS表型的表现的假设需要关键的端粒缩短，端粒长度通过WRN - / - MTERC - / - 小鼠的连续间交叉缩短了遗传缩短。具有短功能失调端粒的复合突变小鼠表现出衰老表型的早期发作，包括脱发，白内障形成和葡萄糖不耐症，并过早死亡。这些令人兴奋的结果表明，我们的小鼠模型概括了在人类患者中观察到的WS的特征。我们的近期目标是表征这些小鼠中的其他衰老表型，并将过早衰老的发作与端粒功能障碍引起的基因组不稳定性相关。我们还正在探测可能导致小鼠模型中观察到的衰老表型的分子机制。这些研究应阐明WRN和功能障碍端粒在人类衰老中的作用。