Immortal DNA Strand and Cardiac Stem Cell Aging

不朽的 DNA 链与心脏干细胞衰老

• 批准号: 8108001
• 负责人: Piero Anversa
• 金额: $ 50.34万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8108001
• 关键词: Address; Adult; Affect; Age; Age of Onset; Aging; Animal Model; Birth; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cell Aging; Cell Count; Cell Differentiation process; Cell Fraction; Cells; Cessation of life; Characteristics; Chromatids; Commit; Coronary Arteriosclerosis; Coronary Vessels; DNA; DNA biosynthesis; Data; Date of birth; Daughter; Defect; Development; Diabetes Mellitus; Disease; Elderly; Endothelial Cells; Environmental Risk Factor; Etiology; Evolution; Fibroblasts; Genomics; Goals; Growth; Harvest; Heart; Heart Diseases; Heart failure; Homeostasis; Human; Human Biology; Human Identifications; Hypertension; In Vitro; Inherited; Lead; Length; Life; Life Cycle Stages; Live Birth; Longevity; Methodology; Modality; Molecular; Mothers; Muscle Cells; Mutation; Myocardial; Myocardium; Myopathy; Natural regeneration; Organ; Organism; Pathology; Pattern; Phenotype; Play; Process; Proto-Oncogene Protein c-kit; Relative (related person); Research; Residual state; Risk Factors; Role; Stem cells; Testing; Time; Treatment Efficacy; Ventricular; Work; Youth; age effect; base; cell age; cell growth; clinically relevant; daughter cell; human disease; interest; novel strategies; prevent; repaired; restoration; segregation; self-renewal; senescence; stem cell division; telomere; theories

DESCRIPTION (provided by applicant): Our central hypothesis is that myocardial aging alone or together with cardiac pathology is dictated by depletion of human cardiac stem cells (hCSCs) with loss of growth reserve for organ homeostasis and repair. The identification of a class of hCSCs with enhanced ability for myocyte and vessel regeneration would have significant implications in delaying or reversing myocardial aging with restoration of the youth of the organ. The possibility that non-random chromatid segregation regulates stem cell division would prevent the acquisition of genomic mutations and telomere attrition during DNA replication. These processes cannot be avoided with random DNA template segregation, in which the old and new DNA strands are acquired by the daughter cell. The growth potential of stem cells possessing the old DNA is theoretically superior to that of stem cells inheriting only the newly synthesized DNA. However, whether this is an all-or-none phenomenon that applies to all organs and the heart in particular is unknown. Several critical issues have to be addressed, concerning the notion of asymmetric segregation of chromatids during stem cell division. They include: a) the actual primitive state of cells carrying the immortal DNA; b) the real length of telomere in cells with the "mother" DNA; c) the lack of quantitative estimates of the fraction of cells dividing by symmetric versus asymmetric chromatid segregation; and d) the molecular basis determining the enhanced growth reserve of hCSCs with the old DNA. These variables impose a reevaluation of the strategies implemented in the identification of hCSCs. Importantly, the etiology of the aging myopathy is unknown and defects in hCSCs may condition the senescent cardiac phenotype, which together with cardiac diseases, may lead to severe ventricular decompensation. On this premise, the role of symmetric stem cell division and fate, i.e., random DNA template segregation, and asymmetric stem cell division and fate, i.e., non-random DNA template segregation, will have to be determined to characterize the contribution of hCSC growth and differentiation to the development of the old failing heart. PUBLIC HEALTH RELEVANCE: This research aims at the identification of the most powerful resident cardiac stem cell present in the human heart. If successful, novel strategies for the treatment of the senescent failing heart will be identified. Additionally, the aging myopathy might be reversed with restoration of the youth of the organ.

描述（由申请人提供）：我们的中心假设是，心肌衰老单独或与心脏病理学一起是由人类心脏干细胞（hCSC）的消耗以及器官稳态和修复的生长储备的丧失决定的。鉴定出一类具有增强的心肌细胞和血管再生能力的hCSC对于延缓或逆转心肌衰老以及恢复器官的年轻具有重要意义。非随机染色单体分离调节干细胞分裂的可能性将防止 DNA 复制过程中基因组突变和端粒磨损的获得。这些过程无法通过随机 DNA 模板分离来避免，其中新旧 DNA 链由子细胞获得。理论上，拥有旧DNA的干细胞的生长潜力优于仅继承新合成DNA的干细胞。然而，这是否是一种适用于所有器官（尤其是心脏）的全有或全无现象尚不清楚。必须解决几个关键问题，涉及干细胞分裂过程中染色单体不对称分离的概念。它们包括： a) 携带不朽DNA的细胞的实际原始状态； b) 具有“母体”DNA 的细胞中端粒的实际长度； c) 缺乏对对称与不对称染色单体分离的细胞比例的定量估计； d) 决定旧 DNA 增强 hCSC 生长储备的分子基础。这些变量要求对 hCSC 识别中实施的策略进行重新评估。重要的是，衰老性肌病的病因尚不清楚，hCSC 的缺陷可能会影响衰老的心脏表型，这与心脏病一起可能导致严重的心室失代偿。在此前提下，必须确定对称干细胞分裂和命运（即随机 DNA 模板分离）和不对称干细胞分裂和命运（即非随机 DNA 模板分离）的作用，以表征 hCSC 生长的贡献以及分化旧有衰竭心脏的发展。 公共健康相关性：这项研究旨在鉴定人类心脏中存在的最强大的驻留心脏干细胞。如果成功，将确定治疗衰老衰竭心脏的新策略。此外，衰老的肌病可能会随着器官的年轻化而逆转。