The role of the telomere capping protein POT1 in mammalian aging

端粒加帽蛋白POT1在哺乳动物衰老中的作用

• 批准号: 7429666
• 负责人: Sandy S Chang
• 金额: $ 30.94万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7429666
• 关键词: Address; Adult; Age; Age of Onset; Aging; Aging-Related Process; Binding; Biological Markers; Bone Density; Cell Aging; Cell Cycle Arrest; Cell Cycle Progression; Cell Proliferation; Cell Survival; Cells; Cessation of life; Chromosome abnormality; Complex; DNA Damage; DNA damage checkpoint; DNA repair protein; Disease; Dyskeratosis Congenita; Event; Exposure to; Functional disorder; Genes; Genetic; Genome Stability; Genomic Instability; Homeostasis; Human; Incidence; Knockout Mice; Laboratories; Lead; Length; Link; Longevity; Maintenance; Malignant Neoplasms; Molecular; Mus; Mutation; Organ; Pancytopenia; Pathology; Pathway interactions; Phenotype; Play; Premature aging syndrome; Process; Proteins; Recruitment Activity; Role; Signal Transduction; Single-Stranded Telomere-Binding Proteins; Site; Stem cells; TP53 gene; Telomerase; Telomere Capping; Telomere Maintenance; Telomere Shortening; Telomere-Binding Proteins; Testing; Tissues; Tumor Tissue; Tumor-Derived; Wound Healing; age related; base; cohort; end of life; glucose tolerance; in vivo; insight; mouse model; recombinase; repaired; research study; response; senescence; small hairpin RNA; telomere; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Elucidating the mechanism of how telomere attrition limits cellular proliferation has important implications for the normal human aging process. Progressive telomere shortening induces replicative senescence, and mice possessing dysfunctional telomeres have reduced life spans. These results strongly implicate a role for telomere dysfunction in both cellular and organismal aging. We have studied the telomere binding protein Potla (protection of telomeres 1a) and found that it is a main determinant of the protective states of telomeres. Pot1 is a single-stranded telomere binding protein that is essential for chromosomal end protection and telomere length homeostasis. Using a Potla conditional knockout mouse generated recently in my laboratory, we show that deletion of Potla induces a DNA damage response that triggers a senescence phenotype indistinguishable from replicative senescence. Loss of Potla also results in extensive chromosomal fusions, suggesting that this protein is required to protect the 3' telomeric overhang from inducing p53-dependent cell cycle arrest. In this proposal, we will use the Potla conditional knockout mouse to test the hypothesis that deletion of Potla results in telomere uncapping and activation of the DNA damage response to initiate cellular senescence and premature aging in vivo. In Aim 1, we will test the hypothesis that loss of Potla leads to telomere deprotection to signal components of the DNA damage pathway to initiate cellular senescence. In Aim 2, we will determine whether conditional deletion of Potla in diverse adult tissues results in the onset of cellular senescence, and whether accumulation of senescent cells result in the onset of aging phenotypes in vivo. We will study several aging phenotypes, including longevity, glucose tolerance, bone density, wound healing, and tumor incidence, over the natural lifespan of these mouse cohorts. In Aim 3, we will determine the level of telomere dysfunction and genomic instability in Potla deficient mice to temporally correlate the onset of premature aging phenotypes with elevated telomere dysfunction and DNA damage response. Our proposal should reveal how telomere uncapping impacts upon both cellular and mammalian aging processes. Given increasing evidence that telomere attrition reduces lifespan in humans, we believe our findings will be relevant to human aging as well.

描述(由申请人提供)：阐明端粒磨损如何限制细胞增殖的机制对正常的人类衰老过程具有重要的意义。进行性端粒缩短会导致复制衰老，而端粒功能障碍的小鼠寿命会缩短。这些结果强烈暗示了端粒功能障碍在细胞和组织衰老中的作用。我们研究了端粒结合蛋白Potla(端粒保护1a)，发现它是端粒保护状态的主要决定因素。POT1是一种单链端粒结合蛋白，对染色体末端保护和端粒长度稳态是必不可少的。使用我实验室最近培育的Potla条件性基因敲除小鼠，我们证明了Potla基因的缺失会引发DNA损伤反应，从而触发与复制衰老无法区分的衰老表型。Potla的缺失还会导致广泛的染色体融合，这表明该蛋白是保护3‘端突起免受诱导依赖于P53的细胞周期停滞所必需的。在这个方案中，我们将使用Potla条件基因敲除小鼠来检验这一假设，即Potla基因的缺失会导致端粒去封顶和DNA损伤反应的激活，从而在体内启动细胞衰老和过早衰老。在目标1中，我们将检验这一假说，即Potla的丢失导致端粒失去保护，从而启动DNA损伤途径的信号成分，从而启动细胞衰老。在目标2中，我们将确定在不同的成人组织中条件性缺失是否会导致细胞衰老的开始，以及衰老细胞的积累是否会导致体内衰老表型的开始。我们将研究几种衰老表型，包括寿命、糖耐量、骨密度、伤口愈合和肿瘤发生率，在这些小鼠的自然寿命范围内。在目标3中，我们将确定Potla缺陷小鼠的端粒功能障碍和基因组不稳定性的水平，以在时间上将过早衰老的表型与端粒功能障碍和DNA损伤反应的升高联系起来。我们的建议应该揭示端粒去封顶如何影响细胞和哺乳动物的衰老过程。鉴于越来越多的证据表明端粒磨损会减少人类的寿命，我们相信我们的发现也将与人类衰老相关。