Redefining Human Myocardial Biology

重新定义人类心肌生物学

• 批准号: 8607586
• 负责人: Piero Anversa
• 金额: $ 52.76万
• 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: 2011-02-15 至 2015-02-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8607586
• 关键词: Adult; Affect; Age; Age Distribution; Aging; Animal Model; Biology; Birth; Blood Vessels; CDKN2A gene; Calcium; Cardiac; Cardiac Myocytes; Cell Cycle; Cell physiology; Cells; Cellular Structures; Cessation of life; Characteristics; Chronic; Clinical; Complex; Comprehension; Coronary; Coronary Vessels; DNA Damage; Data; Date of birth; Defect; Development; Diabetes Mellitus; Differentiation and Growth; Disease; Documentation; Drosophila genus; Embryonic Development; Embryonic Heart; Employee Strikes; Endothelial Cells; Failure; Female; Fetal Heart; Functional disorder; Generations; Genes; Goals; Growth; Health; Heart; Heart failure; Homeostasis; Human; Hypertension; Hypertrophy; In Vitro; Injury; Knowledge; Laboratories; Life; Longevity; Lower Organism; Mammals; Mechanics; Mediating; Mitotic; Molecular; Mus; Muscle Cells; Myocardial; Myocardium; Myopathy; Natural regeneration; Nematoda; Organ; Organism; Pathology; Phase I Clinical Trials; Phenotype; Phosphotransferases; Physiological; Population; Pregnancy; Process; Property; Protocols documentation; Rattus; Recovery of Function; Rodent; Role; Signal Pathway; Smooth Muscle Myocytes; Staging; Stem cells; Stress; Telomerase; Time; Tissues; Translating; Ventricular; Woman; Work; Zebrafish; cell growth; conditioning; defined contribution; hemodynamics; human disease; in vivo; loss of function; male; mathematical model; men; migration; normal aging; novel; novel therapeutics; postnatal; prenatal; public health relevance; repaired; response; self-renewal; senescence; stem cell population; stem cell therapy; telomere

DESCRIPTION (provided by applicant): Current understanding of the cellular processes implicated in the maturation, homeostasis and repair of the human heart is extremely deficient and the need for basic information is striking. Findings in nematodes, fruit flies, zebra fish and rodents have often been translated to human beings with little caution, emphasizing the necessity to study the fundamental principles that regulate the plasticity of the myocardium during the lifespan of women and men. Moreover, the mechanisms modulating the response of the female and male heart to ischemic and non-ischemic myocardial injury and the principal factors conditioning end-stage heart failure and death in humans are at present unknown. This may explain why the astonishing advancements made in cardiac biology experimentally have had so far little impact on the management of the human disease. Thus, the major objectives of this application are: a) To define the contribution of human cardiac stem cells (hCSCs) to the physiological growth of the heart postnatally; b) To establish the rate of myocyte and non-myocyte turnover mediated by hCSC activation and differentiation, together with the analysis of the functional properties of myocytes, in the developing, adult, aging and failing heart; and c) To identify the role of hCSCs in the aging myopathy and heart failure to answer the question whether ventricular decompensation is a stem cell disease. To achieve these goals, we will employ five distinct protocols: a) Retrospective 14C birth dating of cardiac cells to establish the average age of myocytes and non-myocytes; b) A mathematical model of age- structured cell populations to define the age distribution of myocytes and non-myocytes; c) A mathematical model of hierarchically organized cells to assess the rate of formation of myocytes and non-myocytes by lineage commitment of hCSCs; d) hCSC and myocyte senescence by the expression of p53 and p16INK4a, and the accumulation of DNA damage and telomere dysfunction induced foci (TIFs) to determine the integrity of the telomere-telomerase axis; and e) The mechanical, electrical and calcium transient characteristics of myocytes to evaluate the effects of parenchymal cell physiology on ventricular hemodynamics. These five sets of complementary data will offer a novel comprehensive perspective of the cellular processes which govern the lifespan of the human heart. This information is critical for the recognition of the mechanisms that control the dynamics of the human heart, its reserve, adaptation to stress and failure.

描述（由申请人提供）： 目前对涉及人类心脏成熟、稳态和修复的细胞过程的理解是极其缺乏的，对基本信息的需求是惊人的。在线虫、果蝇、斑马鱼和啮齿动物中的发现经常被不加小心地翻译到人类身上，强调有必要研究在女性和男性的生命周期中调节心肌可塑性的基本原则。此外，调节女性和男性心脏对缺血性和非缺血性心肌损伤的反应的机制以及人类终末期心力衰竭和死亡的主要因素目前尚不清楚。这也许可以解释为什么迄今为止，心脏生物学在实验上取得的惊人进步对人类疾病的管理几乎没有影响。因此，本申请的主要目的是：a）确定人心脏干细胞（hCSC）对出生后心脏的生理生长的贡献; B）确定在发育、成年、老化和衰竭的心脏中由hCSC活化和分化介导的肌细胞和非肌细胞更新的速率，以及分析肌细胞的功能特性;和c）鉴定hCSC在衰老性肌病和心力衰竭中的作用，以回答心室失代偿是否是干细胞疾病的问题。为了实现这些目标，我们将采用五种不同的方案：a）心肌细胞的回顾性14 C出生日期以建立肌细胞和非肌细胞的平均年龄; B）年龄结构细胞群的数学模型以定义肌细胞和非肌细胞的年龄分布; c）分层组织细胞的数学模型，以通过hCSC的谱系定型评估肌细胞和非肌细胞的形成速率; d）通过p53和p16 INK 4a的表达的hCSC和肌细胞衰老，以及DNA损伤和端粒功能障碍诱导的病灶（TIF）的积累，以确定端粒-端粒酶轴的完整性;和e）肌细胞的机械、电和钙瞬变特征，以评估实质细胞生理学对心室血流动力学的影响。这五组互补数据将为控制人类心脏寿命的细胞过程提供一个新的全面视角。这些信息对于认识控制人类心脏动力学的机制、其储备、对压力和失败的适应至关重要。