Immortal DNA Strand and Cardiac Stem Cell Aging

不朽的 DNA 链与心脏干细胞衰老

• 批准号: 8309068
• 负责人: Piero Anversa
• 金额: $ 50.35万
• 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/8309068
• 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.

描述（由申请人提供）：我们的中心假设是，心肌老化单独或与心脏病理学一起由人心脏干细胞（hCSC）耗竭以及器官稳态和修复的生长储备丧失决定。鉴定一类具有增强的肌细胞和血管再生能力的hCSC将在延迟或逆转心肌老化以及恢复器官的年轻性方面具有重要意义。非随机染色单体分离调节干细胞分裂的可能性将防止在DNA复制期间获得基因组突变和端粒磨损。这些过程不能通过随机DNA模板分离来避免，其中旧的和新的DNA链被子细胞获得。拥有旧DNA的干细胞的生长潜力理论上上级于只继承新合成DNA的干细胞。然而，这是否是一种适用于所有器官，特别是心脏的全或无现象尚不清楚。关于干细胞分裂过程中染色单体不对称分离的概念，有几个关键问题需要解决。它们包括：a）携带永生DNA的细胞的实际原始状态; B）具有“母亲”DNA的细胞中端粒的真实的长度; c）缺乏对通过对称与不对称染色单体分离分裂的细胞分数的定量估计;和d）确定具有旧DNA的hCSC的生长储备增强的分子基础。这些变量迫使重新评估在鉴定hCSC中实施的策略。重要的是，衰老性肌病的病因学是未知的，并且hCSC中的缺陷可以调节衰老的心脏表型，其与心脏疾病一起可以导致严重的心室失代偿。在此前提下，对称干细胞分裂和命运的作用，即，随机的DNA模板分离，以及不对称的干细胞分裂和命运，即，非随机DNA模板分离，将必须被确定以表征hCSC生长和分化对老年衰竭心脏的发展的贡献。