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Telomere replication and maintenance of genome stability

端粒复制和基因组稳定性的维持

基本信息

批准号：
8696978
负责人：
Sandy S Chang
金额：
$ 20.81万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
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/8696978
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&apos 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

项目摘要

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)：涉及人类衰老和相关器官退化的分子机制和遗传途径尚不清楚。人类衰老与许多高增殖性组织的功能缺陷有关。这些组织必须不断地由组织干细胞补充，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，需要更多地了解干细胞功能在人类衰老过程中是如何改变的。使用小鼠模型和人类细胞系的研究表明，维持端粒稳态对干细胞功能至关重要。端粒是一种核蛋白结构，在维持染色体完整性和基因组稳定性方面发挥着重要作用。在哺乳动物中，端粒由TTAGGG重复序列组成，由端粒酶维持。端粒酶在人类体细胞中是限制性的，导致进行性端粒缩短。端粒功能障碍不再发挥末端保护功能的端粒被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来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复制过程中构成了一个独特的问题，因为它们类似于脆弱部位。这一建议解决了端粒生物学中一个很大程度上未被探索的领域--适当的端粒复制在维持基因组稳定和细胞内稳态方面发挥了什么作用？我们的建议是创新的，因为它解决了这样的假设，即未能正确复制端粒可能与端粒酶缺陷一样重要，从而产生不稳定的基因组。