Telomere replication and maintenance of genome stability

端粒复制和基因组稳定性的维持

• 批准号: 8582453
• 负责人: Sandy S Chang
• 金额: $ 24.98万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-15 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8582453
• 关键词: Address; Aging; Aging-Related Process; Area; Biochemical; Biogenesis; Biology; Bone Marrow; Bone Marrow Cells; Cell Proliferation; Cell Survival; Cell Transplants; Cell physiology; Cells; Chromosome Fragile Sites; Chromosomes; Coats' disease; Complex; DNA; DNA Damage; DNA Double Strand Break; DNA Repair; DNA biosynthesis; Defect; Disease; Dyskeratosis Congenita; Elderly; Embryo; Enzymes; Eukaryota; Failure; Family history of; Fibroblasts; Functional disorder; Genetic; Genome; Genome Stability; Goals; Hematopoietic stem cells; Homeostasis; Human; Human Cell Line; Knockout Mice; Life; Maintenance; Mammals; Mediating; Molecular; Mus; Mutation; Nucleoproteins; Organ; Pancytopenia; Pathogenesis; Pathway interactions; Patients; Phenotype; Play; Premature aging syndrome; Proliferating; Proteins; Publishing; Recruitment Activity; Repetitive Sequence; Reporting; Repression; Retinal; Role; Somatic Cell; Stem cells; Structure; TINF2 gene; Techniques; Telangiectasis; Telomerase; Telomere Maintenance; Telomere Shortening; Telomere-Binding Proteins; Testing; Tissues; Transplantation; calcification; human disease; innovation; insight; member; mouse model; mutant; normal aging; novel; prevent; protein complex; public health relevance; reconstitution; research study; response; self-renewal; telomere

DESCRIPTION (provided by applicant): The molecular mechanisms and genetic pathways involved in human aging and associated organ degeneration are not well understood. Human aging is associated with functional defects in many highly proliferative tissues. These tissues must be continuously replenished by tissue stem cells, since differentiated cells are lost throughout life. Increasing evidence suggests that the normal human aging process is associated with a decline in stem cell function. Therefore, to devise approaches to help ameliorate the pathological effects of the normal aging process, a greater understanding of how stem cell functions are altered during human aging is required. Studies using mouse models and human cell lines point to the maintenance of telomere homeostasis as critical for stem cell function. Telomeres are nucleoprotein structures that play essential roles in maintaining chromosome integrity and genome stability. In mammals, telomeres consist of TTAGGG repetitive sequences and are maintained by the enzyme telomerase. Telomerase is limiting in human somatic cells, resulting in progressive telomere shortening. Dysfunctional telomeres that can no longer exert end-protective functions are recognized as DNA double stranded breaks by the DNA damage repair (DDR) pathway. While telomere repeats are used by eukaryotes to solve the end replication problem and confers chromosome end protective functions, they pose a unique problem during DNA replication since they resemble fragile sites. This proposal addresses a largely unexplored area of telomere biology-what impact does proper telomere replication play in the maintenance of genome stability and cellular homeostasis? Our proposal is innovative because it addresses the hypothesis that failure to properly replicate telomeres may be as important as telomerase deficiency to generate an unstable genome.

描述（由申请人提供）：人类衰老和相关器官退化的分子机制和遗传途径尚未得到很好的理解。人类衰老与许多高度增殖组织的功能缺陷有关。这些组织必须由组织干细胞不断补充，因为分化的细胞在整个生命过程中都会丢失。越来越多的证据表明，正常的人类衰老过程与干细胞功能的下降有关。因此，为了设计方法来帮助改善正常衰老过程的病理影响，需要更好地了解干细胞功能在人类衰老过程中如何改变。使用小鼠模型和人类细胞系的研究指出端粒稳态的维持对于干细胞功能至关重要。端粒是核蛋白结构，在维持染色体完整性和基因组稳定性方面发挥重要作用。在哺乳动物中，端粒由TTAGGG重复序列组成，并由端粒酶维持。端粒酶是限制在人体细胞，导致进行性端粒缩短。不能再发挥末端保护功能的功能失调的端粒被DNA损伤修复（DDR）途径识别为DNA双链断裂。虽然端粒重复序列被真核生物用于解决末端复制问题并赋予染色体末端保护功能，但它们在DNA复制过程中造成了独特的问题，因为它们类似于脆弱位点。这个提议涉及到端粒生物学中一个很大程度上未被探索的领域--端粒的正确复制在维持基因组稳定性和细胞内稳态中发挥什么样的作用？我们的建议是创新的，因为它解决了一个假设，即未能正确复制端粒可能与端粒酶缺陷一样重要，以产生不稳定的基因组。