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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

基本信息

批准号：
8514462
负责人：
Annarosa Leri
金额：
$ 31.92万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
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/8514462
关键词：
8-hydroxy-2&apos -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

项目摘要

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.

描述（由申请人提供）：认识到心脏具有形成心肌细胞和冠状血管的干细胞室，增加了心脏祖细胞（CPCs）数量和/或功能改变的可能性，使衰老性肌病的发病成为条件。常驻心肌细胞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。CPCs的生命周期似乎受端粒酶活性和端粒长度的调节；端粒缩短超过临界长度会引发细胞衰老和死亡。尽管端粒磨损在细胞衰老中的作用已在体外得到证实，但在体内端粒DNA的丢失是否会导致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)体内心肌衰老过程中端粒缩短是否发生；b)端粒极短的cpc发生复制性衰老和凋亡；端粒缩短导致干细胞和心肌细胞老化，最终导致心力衰竭。我们将尝试通过首先采用动物模型来回答这些问题，其中端粒侵蚀依赖于端粒酶RNA成分的缺失。随后，我们将研究人类细胞的端粒酶-端粒轴（hcpc），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可防止端粒磨损并增强端粒酶活性，而Ang II可促进hcpc的氧化应激。因此，我们将利用IGF-1受体（IGF-1R）和Ang II受体1 （AT1R）分别分离端粒长和端粒短的hcpc。IGF-1R和AT1R在hcpc中的作用可能是由它们对p53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衰老和心脏老化目前尚不清楚。我们将重点关注p53、miR-34和miR-34靶基因之间的相互作用；miR-34是p53的下游效应物，被认为是CPC和心脏衰老的重要决定因素。