Telomeric Shortening, p53 and miR-34a Condition Senescence of Cardiac Progenitors

端粒缩短、p53 和 miR-34a 影响心脏祖细胞的衰老

• 批准号: 8310953
• 负责人: Annarosa Leri
• 金额: $ 33.78万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8310953
• 关键词: 8-hydroxy-2' -deoxyguanosine; Abbreviations; Adult; Affect; Age; Age of Onset; Aging; Angiotensin II; Angiotensin II Receptor; Angiotensinogen; Animal Model; Animals; Apoptosis; Binding; Bone Marrow; CDKN2A gene; Cardiac; Cardiac Myocytes; Cell Aging; Cell Proliferation; Cell physiology; Cells; Cessation of life; Chronic; Conflict (Psychology); Contracts; Coronary Vessels; Coupled; DNA; DNA Damage; Deoxyguanosine; Differentiation and Growth; Disease; Down-Regulation; Dropout; Elderly; Endothelial Cells; Epigenetic Process; Failure; Fluorescent in Situ Hybridization; Gene Targeting; Genes; Goals; Growth; Heart; Heart Diseases; Heart failure; Hepatocyte Growth Factor; Homeostasis; Human; In Vitro; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Insulin-Like Growth Factor Receptor; Insulin-Like-Growth Factor I Receptor; Laboratories; Length; Life Cycle Stages; Ligands; Mediating; Mus; Muscle Cells; Myocardial; Myocardium; Myopathy; Natural regeneration; Organ; Organism; Oxidative Stress; Pathway interactions; Phenotype; Play; Population; Population Heterogeneity; Property; Proteins; Protocols documentation; RNA; RNA-Directed DNA Polymerase; Reactive Oxygen Species; Receptor Protein-Tyrosine Kinases; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Role; Scheme; Smooth Muscle Myocytes; Stem cells; Stromal Cell-Derived Factor 1; Telomerase; Telomerase RNA Component; Telomere Shortening; Testing; Time; Tissues; age effect; aged; cell age; cell growth; derepression; gene repression; human IGF2R protein; in vivo; migration; novel strategies; oxidative damage; pressure; prevent; primitive cell; progenitor; public health relevance; receptor; regenerative; repaired; senescence; telomere; transcription factor

DESCRIPTION (provided by applicant): The recognition that the heart possesses a stem cell compartment that forms myocytes and coronary vessels raises the possibility that alterations in number and/or function of cardiac progenitor cells (CPCs) condition the onset of the aging myopathy. The decline in regenerative capacity of resident CPCs may dictate the accumulation of old myocytes and the cardiac senescent phenotype. The life cycle of CPCs appears to be regulated by telomerase activity and telomere length; shortening of telomeres beyond a critical length triggers cellular senescence and death. Although the role of telomere attrition in cellular aging has been documented in vitro, it remains to be determined whether loss of telomere DNA leads to organ and organism aging in vivo. Thus, our major goal is to assess whether: a) telomere shortening occurs during myocardial aging in vivo; b) CPCs with critically short telomeres undergo replicative senescence and apoptosis; and c) telomere shortening causes stem cell and myocyte aging and ultimately heart failure. We will attempt to answer these questions by employing first an animal model in which telomere erosion depends on the deletion of the RNA component of telomerase. Subsequently, we will study the telomerase-telomere axis in human CPCs (hCPCs) and establish whether telomerase activity and telomere length modulate the growth properties of these cells. Evidence in our laboratory suggests that IGF-1 prevents telomere attrition and enhances telomerase activity while Ang II promotes oxidative stress in hCPCs. Therefore, IGF-1 receptor (IGF-1R) and Ang II receptor 1 (AT1R) will be employed to isolate hCPCs with long and short telomeres, respectively. The function of IGF-1R and AT1R in hCPCs may be mediated by their opposite effects on the expression and activity of p53; p53 is expected to be critically involved in hCPC senescence. Whether p53-responsive genes dictate hCPC senescence and cardiac aging is currently unknown. We will focus on the interaction between p53, miR-34 and miR-34 target genes; miR-34 is a downstream effector of p53 and is proposed to be an important determinant of CPC and cardiac aging. PUBLIC HEALTH RELEVANCE: Senescence of cardiac progenitor cells is a critical determinant of the aging myopathy. A new approach is proposed here for the identification of progenitor cells which may have a significant capacity to divide and form a large number of cardiomyocytes. If successful, this strategy may have important implications for the management of human heart failure in the elderly.

描述（由申请人提供）：认识到心脏具有形成肌细胞和冠状血管的干细胞区室，提出了心脏祖细胞（CPC）数量和/或功能的改变调节衰老性肌病发作的可能性。常驻CPC再生能力的下降可能决定了衰老心肌细胞的积累和心脏衰老表型。CPC的生命周期似乎受到端粒酶活性和端粒长度的调节;端粒缩短超过临界长度会触发细胞衰老和死亡。虽然端粒磨损在细胞衰老中的作用已经在体外被证明，但端粒DNA的丢失是否会导致体内器官和生物体衰老仍有待确定。因此，我们的主要目标是评估：a）端粒缩短是否发生在体内心肌老化过程中; B）具有临界短端粒的CPC经历复制性衰老和凋亡;以及c）端粒缩短是否导致干细胞和肌细胞老化并最终导致心力衰竭。我们将尝试回答这些问题，首先采用动物模型，其中端粒侵蚀依赖于端粒酶RNA成分的缺失。随后，我们将研究人CPC（hCPC）中的端粒酶-端粒轴，并确定端粒酶活性和端粒长度是否调节这些细胞的生长特性。我们实验室的证据表明，IGF-1防止端粒磨损和增强端粒酶活性，而血管紧张素II促进hCPC中的氧化应激。因此，IGF-1受体（IGF-1 R）和Ang II受体1（AT 1 R）将分别用于分离具有长和短端粒的hCPC。IGF-1 R和AT 1 R在hCPC中的功能可能是通过它们对p53的表达和活性的相反作用介导的; p53预计在hCPC衰老中起关键作用。p53应答基因是否决定hCPC衰老和心脏衰老目前尚不清楚。我们将关注p53、miR-34和miR-34靶基因之间的相互作用; miR-34是p53的下游效应子，被认为是CPC和心脏衰老的重要决定因素。 公共卫生关系： 心脏祖细胞的衰老是衰老性肌病的关键决定因素。本文提出了一种新的方法来鉴定祖细胞，这些祖细胞可能具有显著的分裂和形成大量心肌细胞的能力。如果成功，这种策略可能对老年人心力衰竭的管理具有重要意义。