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: 7456340
• 负责人: Eric J Brown
• 金额: $ 26.98万
• 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/7456340
• 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，已经提出了基因组完整性的逐渐丧失来促进衰老过程。与该理论一致，涉及维持基因组完整性的基因突变通常会导致过早衰老。确定对年龄相关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如何指导我们更好地预测，诊断和减慢这些疾病的发作的能力。 ATR蛋白激酶在哺乳动物细胞中保持基因组完整性，是细胞周期检查点的中心调节剂。使用CRE/LOX系统，该系统允许在2-3个月大的成年小鼠中有条件地删除ATR基因，我们的初步工作表明，ATR删除后3-6个月出现了几种与年龄相关的表型。这些衰老的表型包括脱发，头发灰色，脑膜病，骨质疏松症，心肌病，睾丸萎缩和急性免疫抑制。借助这种独特的小鼠模型，我们建议在本文中证实这些初始发现，并进一步探讨ATR在预防与年龄有关的疾病中的作用。提出了实验以进一步探索ATR损失对几种疾病的影响，这些疾病是人类衰老的成分（脱发和灰色，骨质疏松症以及造血再生能力的降低），并且重要的是，是否是由ATRETENED DEDETION和/或直接效果的再生能力引起的，以解决这些表型是否引起。为了确定p53转录因子的激活是否在ATR缺失引起的年龄相关表型中起因作用，将在ATR小鼠中观察到的过早衰老与缺乏ATR和p53的小鼠中观察到的过早衰老。最后，提出了实验，该实验将确定是否因ATR损失而加剧了由正常代谢过程导致的氧化DNA碱基损伤，从而导致剧毒DNA双链断裂。 DNA损伤的这种扩增可能会加速正常衰老。为了检验这一假设，通过调节细胞内羟基自由基浓度在ATR基因敲除细胞中的治疗方法将减少或增加氧化性DNA损伤，这些治疗的效果将通过染色体扩散分析来监测。这些研究将寻求分子理解ATR缺失如何导致过早衰老。