The role of ATR in preventing age-related diseases

ATR 在预防年龄相关疾病中的作用

• 批准号: 7259328
• 负责人: Eric J Brown
• 金额: $ 28.04万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-15 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7259328
• 关键词: ATR gene; ATR protein kinase; Acute; Address; Age; Aging; Aging-Related Process; Alopecia; Animals; Appearance; Appendix; Atrophic; Biological Models; Cardiomyopathies; Cell Cycle Checkpoint; Cells; Cessation of life; Chromosomal Breaks; Chromosomal Instability; Chromosome Breakage; Chromosomes; DBL Oncoprotein; DNA; DNA Damage; DNA Double Strand Break; DNA biosynthesis; DNA replication fork; Diagnosis; Disease; Elderly; Gene Mutation; Genetic; Genetic Determinism; Genetic Predisposition to Disease; Genome; Genomics; Gray unit of radiation dose; Hair; Hematopoietic; Human; Hydroxyl Radical; Immune; Knock-out; Knockout Mice; Kyphosis deformity of spine; Laboratories; Lead; Maintenance; Mammalian Cell; Metabolism; Methods; Mitochondria; Mitotic; Molecular; Monitor; Mus; Onset of illness; Osteoporosis; Phenotype; Play; Premature aging syndrome; Range; Research; Respiration; Role; System; TP53 gene; Testing; Tissues; Work; age related; base; design; in vivo; knockout animal; mouse model; normal aging; oxidative DNA damage; prevent; research study; response; theories; transcription factor; treatment effect

DESCRIPTION (provided by applicant): A gradual loss of genomic integrity has long been proposed to contribute to the aging process. Consistent with this theory, mutation of genes involved in maintaining genome integrity often leads to premature aging. Identifying the potential genetic predispositions to age-related diseases and, more importantly, understanding how these genetic determinants lead to disease will likely guide our ability to better predict, diagnose and slow the onset of these disorders. The ATR protein kinase maintains genome integrity in mammalian cells and is a central regulator of cell cycle checkpoints. Using a cre/lox system that allows conditional deletion of the ATR gene in 2-3 month old adult mice, our preliminary work has demonstrated that several age-related phenotypes appear 3-6 months after ATR deletion. These aging phenotypes include alopecia, hair graying, kyphosis, osteoporosis, cardiomyopathy, testicular atrophy and acute immune suppression. With this unique mouse model, we propose herein to substantiate these initial findings and further explore the role of ATR in preventing age-related diseases. Experiments are proposed to further explore the effect of ATR loss on several disorders that are components of human aging (hair loss and graying, osteoporosis and reduced hematopoietic regenerative capacity) and, importantly, to address if these phenotypes are caused by a loss of regenerative capacity following ATR deletion and/or a direct effect on differentiated cells. To determine if activation of the p53 transcription factor plays a causative role in age-related phenotypes that result from ATR deletion, the premature aging observed in ATR mice will be compared with that observed in mice that lack both ATR and p53. Finally, experiments are proposed that will determine whether the oxidative DNA base damage that results from normal metabolic processes is exacerbated by ATR loss, leading to highly toxic DNA double strand breaks. Such amplification of DNA damage may accelerate normal aging. To test this hypothesis, oxidative DNA damage will be reduced or increased by treatments that modulate intracellular hydroxyl radical concentrations in ATR knockout cells, and the effect of these treatments will be monitored by chromosome spread analysis. These studies will seek a molecular understanding of how ATR deletion leads to premature aging.

描述（由申请人提供）：长期以来一直认为基因组完整性的逐渐丧失会导致衰老过程。与这一理论相一致的是，参与维持基因组完整性的基因突变通常会导致过早衰老。确定年龄相关疾病的潜在遗传易感性，更重要的是，了解这些遗传决定因素如何导致疾病，将可能指导我们更好地预测，诊断和减缓这些疾病的发作。ATR蛋白激酶在哺乳动物细胞中维持基因组完整性，并且是细胞周期检查点的中心调节剂。利用cre/lox系统，允许条件删除ATR基因在2-3个月大的成年小鼠，我们的初步工作已经证明，几个年龄相关的表型出现后3-6个月ATR删除。这些老化表型包括脱发、头发变白、脊柱后凸、骨质疏松症、心肌病、睾丸萎缩和急性免疫抑制。有了这个独特的小鼠模型，我们在此建议证实这些初步研究结果，并进一步探索ATR在预防年龄相关疾病中的作用。提出实验以进一步探索ATR损失对作为人类衰老的组成部分的几种病症（脱发和变灰、骨质疏松症和造血再生能力降低）的影响，并且重要的是，解决这些表型是否由ATR缺失后的再生能力损失和/或对分化细胞的直接影响引起。为了确定p53转录因子的激活是否在由ATR缺失引起的年龄相关表型中起致病作用，将在ATR小鼠中观察到的过早衰老与在缺乏ATR和p53的小鼠中观察到的过早衰老进行比较。最后，实验提出，将确定是否从正常的代谢过程中产生的氧化DNA碱基损伤是由ATR损失加剧，导致高毒性的DNA双链断裂。这种DNA损伤的放大可能会加速正常衰老。为了检验这一假设，通过调节ATR敲除细胞中的细胞内羟基自由基浓度的处理将减少或增加氧化性DNA损伤，并且将通过染色体扩散分析来监测这些处理的效果。这些研究将寻求从分子水平上理解ATR缺失如何导致过早衰老。