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Aging of the Heart

心脏的老化

基本信息

批准号：
8588868
负责人：
Piero Anversa
金额：
$ 222.55万
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：
2012
资助国家：
美国
起止时间：
2012-12-01 至 2017-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8588868
关键词：
Adult Affect Age Aging Angiotensin II Animal Model Animals Apoptosis Autologous Behavior Birth Blood Vessels Cardiac Cardiac Myocytes Cell Aging Cell Count Cell Cycle Cell Death Cell physiology Cells Cessation of life Characteristics Cicatrix Conflict (Psychology)Coronary Coronary Vessels DNA Damage Data Defect Diffuse Disease Elderly Endothelial Cells Equilibrium Etiology Feasibility Studies Female Fibroblasts Fibrosis Functional disorder Future Gender Growth Harvest Health Heart Heart failure Human In Vitro Lead Life Live Birth Longevity Microcirculation Mothers Muscle Cells Myocardial Myocardium Myopathy Natural regeneration Organ Organism Oxidative Stress Pathologic Performance Phenotype Process Program Research Project Grants Property Proto-Oncogene Protein c-kit Protocols documentation Receptor, Angiotensin, Type 1 Relaxation Research Role Sarcomeres Sex Characteristics Smooth Muscle Myocytes Stem cells Stretching Structure Supporting Cell Telomerase Telomere Shortening Testing Time Vascular Endothelial Cell Ventricular Dysfunction Ventricular Function Woman aged cell age cell growth conditioning gap junction channel heart function human female human male interstitial male mechanical behavior men novel strategies postnatal prevent public health relevance senescence stem cell therapy telomere young mother

项目摘要

DESCRIPTION (provided by applicant): Currently, we have little understanding of the etiology of myocardial aging. Rarely, studies in animals and humans have considered aging as an independent process and time as the major cause of the aging myopathy. Only occasionally cardiac aging in humans has been characterized independently from concomitant pathologic states. Aging has been interpreted as a variable, which cooperates with a variety of diseases, to define the old, poorly functional heart. This Program Project Grant (PPG) aims at the: a) Definition of myocardial aging; b) Identification of the determinants of the cardiac senescent phenotype; and c) Recognition whether the aging myopathy conditions health and life span. The major hypothesis to be tested is that aging of cardiac stem cells (CSCs) affects the size and properties of the myocyte, vascular, and fibroblast progeny which, in turn, conditions the structure and function of the heart. Aged CSCs may generate a smaller number of senescent myocytes with defects in electrical and mechanical behavior, and a larger number of fibroblasts which, together, underlie diastolic dysfunction and the old cardiac phenotype. This PPG has five objectives: a) To determine whether the adult heart is a self-autonomous organ regulated by the orderly organization and growth of CSCs; b) To determine whether telomeric shortening in CSCs with aging leads to time-dependent changes in the growth properties of CSCs and characteristics of the differentiated progeny; c) To determine whether old CSCs with short telomeres generate functionally-defective myocytes together with enhanced formation of fibroblasts; d) To determine whether accumulation of fibroblasts and myocytes with impaired contractile performance promotes diastolic dysfunction, typically present in the senescent heart; and e) To determine whether strategies preventing the aging myopathy, or reversing myocardial aging can be developed to extend health and life span in the elderly. The common theme of this PPG is understanding the control of CSC growth and commitment, the etiology of CSC senescence and death, and the impact that old CSCs have on the properties of the differentiated progeny The telomere-telomerase axis is viewed as the key regulator of CSC replication, senescence and death, conditioning myocyte, coronary vasculature, and organ aging. Alterations in the turnover rate of cardiomyocytes, vascular cells, and fibroblasts define the aging myopathy. CSCs with preserved function are present in the old heart, and repopulating protocols with CSCs possessing intact telomeres may replace defective myocytes with new, mechanically efficient cells, and restore the coronary vasculature and microvasculature reversing the senescent phenotype, ultimately, prolonging health and life span of the organ and organism. To fulfill these objectives, the role of CSCs in myocardial aging of small (Projects 1 and 2) and large (Project 3) animals and humans (Project 4) will be investigated in an integrated manner to identify the variables that lead to ventricular dysfunction in the old heart.

描述（申请人提供）：目前，我们对心肌老化的病因知之甚少。很少有动物和人类的研究将衰老视为一个独立的过程，而将时间视为衰老性肌病的主要原因。人类的心脏老化只是偶尔独立于伴随的病理状态。衰老被解释为一个变量，它与各种疾病合作，定义了衰老，功能不良的心脏。本计划项目资助（PPG）旨在：a)心肌老化的定义；b)确定心脏衰老表型的决定因素；c)识别老年性肌病是否影响健康和寿命。要验证的主要假设是，心脏干细胞（CSCs）的老化会影响心肌细胞、血管和成纤维细胞后代的大小和特性，进而影响心脏的结构和功能。衰老的CSCs可能产生较少数量的具有电和机械行为缺陷的衰老肌细胞，以及大量的成纤维细胞，这些细胞共同构成舒张功能障碍和老年心脏表型的基础。该PPG有五个目的：a)确定成人心脏是否是一个受CSCs有序组织和生长调节的自主器官；b)确定随着年龄的增长，CSCs的端粒缩短是否会导致CSCs生长特性和分化后代特征的时间依赖性变化；c)确定端粒较短的衰老CSCs是否产生功能缺陷的肌细胞，并增强成纤维细胞的形成；d)确定收缩功能受损的成纤维细胞和肌细胞的积累是否会促进舒张功能障碍，这通常存在于衰老的心脏中；e)确定是否可以制定预防老年性肌病或逆转心肌老化的策略来延长老年人的健康和寿命。本PPG的共同主题是了解CSC生长和承诺的控制，CSC衰老和死亡的病因，以及衰老的CSC对分化后代特性的影响。端粒-端粒酶轴被认为是CSC复制、衰老和死亡、调节心肌细胞、冠状血管和器官衰老的关键调节因子。心肌细胞、血管细胞和成纤维细胞周转率的改变定义了老年性肌病。保留功能的CSCs存在于旧心脏中，具有完整端粒的CSCs的再生方案可以用新的、机械效率高的细胞取代有缺陷的肌细胞，并恢复冠状血管和微血管，逆转衰老表型，最终延长器官和生物体的健康和寿命。为了实现这些目标，我们将以综合的方式研究CSCs在小型（项目1和2）、大型（项目3）动物和人类（项目4）心肌衰老中的作用，以确定导致老年心脏心室功能障碍的变量。