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: 7907272
• 负责人: Eric J Brown
• 金额: $ 13.08万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7907272
• 关键词: ATR gene; ATR protein kinase; Acute; Address; Age; Aging; Aging-Related Process; Alopecia; Animals; Appearance; 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; 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; regenerative; 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，人们一直认为基因组完整性的逐渐丧失会导致衰老过程。与这一理论一致，参与维持基因组完整性的基因突变通常会导致过早衰老。识别与年龄相关的疾病的潜在遗传倾向，更重要的是，了解这些遗传决定因素如何导致疾病，可能会指导我们更好地预测、诊断和减缓这些疾病的发作。 ATR 蛋白激酶维持哺乳动物细胞中的基因组完整性，是细胞周期检查点的中央调节器。使用允许在 2-3 个月大的成年小鼠中条件性删除 ATR 基因的 cre/lox 系统，我们的初步工作表明，在 ATR 删除后 3-6 个月出现了几种与年龄相关的表型。这些衰老表型包括脱发、头发花白、脊柱后凸、骨质疏松、心肌病、睾丸萎缩和急性免疫抑制。通过这种独特的小鼠模型，我们在此提出证实这些初步发现并进一步探索 ATR 在预防与年龄相关的疾病中的作用。建议进行实验以进一步探讨 ATR 丧失对人类衰老的几种疾病（脱发和白发、骨质疏松症和造血再生能力降低）的影响，更重要的是，解决这些表型是否是由再生能力丧失引起的ATR 缺失和/或对分化细胞的直接影响后。为了确定 p53 转录因子的激活是否在 ATR 缺失导致的年龄相关表型中起因果作用，我们将在 ATR 小鼠中观察到的过早衰老与在同时缺乏 ATR 和 p53 的小鼠中观察到的过早衰老进行比较。最后，提出了实验来确定正常代谢过程引起的氧化性 DNA 碱基损伤是否会因 ATR 损失而加剧，从而导致剧毒的 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 敲除细胞内羟自由基浓度的治疗，可以减少或增加氧化性 DNA 损伤，并且通过染色体扩散分析来监测这些治疗的效果。这些研究将寻求从分子角度理解 ATR 缺失如何导致过早衰老。