Redefining Human Myocardial Biology

重新定义人类心肌生物学

基本信息

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
项目类别：
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

项目摘要

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）：目前对人类心脏成熟、稳态和修复所涉及的细胞过程的理解极其不足，对基本信息的需求是惊人的。线虫、果蝇、斑马鱼和啮齿动物的研究结果常常被不加谨慎地转化为人类，这强调了研究在女性和男性一生中调节心肌可塑性的基本原理的必要性。此外，目前尚不清楚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调节人类终末期心力衰竭和死亡的主要因素。这可以解释为什么心脏生物学实验取得的惊人进步迄今为止对人类疾病的治疗影响甚微。因此，本申请的主要目标是： a) 确定人类心脏干细胞 (hCSC) 对出生后心脏生理生长的贡献； b) 确定发育中、成人、衰老和衰竭心脏中 hCSC 激活和分化介导的肌细胞和非肌细胞周转率，并分析肌细胞的功能特性； c) 确定 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 14C 出生日期以确定心肌细胞和非心肌细胞的平均年龄； b) 年龄结构细胞群的数学模型，用于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，用于通过 hCSC 的谱系定向评估心肌细胞和非肌细胞的形成率； d) hCSC和肌细胞通过p53和p16INK4a的表达以及DNA损伤和端粒功能障碍诱导灶（TIF）的积累来判断端粒-端粒酶轴的完整性； e) 肌细胞的机械、电和钙瞬态特性，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新颖的综合视角。这些信息对于识别控制人类心脏动态、其储备、对压力和衰竭的适应的机制至关重要。