Cardiac Stem Cells and Angiomyogenesis

心脏干细胞和血管肌生成

基本信息

批准号：
8218441
负责人：
JAN KAJSTURA
金额：
$ 42.27万
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：
2011-12-02 至 2016-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8218441
关键词：
Adult Age Age-Months Aging Anemia Animals Attenuated Biological Preservation Birth Cardiac Cardiac Myocytes Cell Lineage Cells Chromatids Clonality Commit Contracts Coronary Vessels Cytoplasmic Protein DNA DNA biosynthesis Data Daughter Development Differentiation and Growth Disease Documentation Embryo Embryonic Heart Endothelial Cells Environmental Risk Factor Goals Growth Heart Heart Diseases Heart failure Human Hypertrophy In Vitro Individual Inherited Laboratories Lead Life Life Cycle Stages Longevity Methodology Modeling Mothers Mus Muscle Cells Myocardial Myocardium Myopathy Organ Oxidative Stress Phenotype Process Proliferating Property Proto-Oncogene Protein c-kit Protocols documentation Replication Error Research Role Sister Smooth Muscle Myocytes Stem cells Undifferentiated Vascular Endothelial Cell Viral cardiogenesis cell growth daughter cell fetal in vivo loss of function postnatal prenatal prevent progenitor segregation self-renewal senescence stem cell division theories transcription factor vasculogenesis

项目摘要

DESCRIPTION (provided by applicant): The recognition that a pool of cardiac stem cells (CSCs) is present in the adult myocardium poses the question whether CSCs are responsible for cardiomyogenesis in the embryonic, fetal and postnatal heart, regulate myocyte renewal in the adult organ and condition myocardial aging. Stem cell renewal occurs by symmetric division, which generates two daughter stem cells, or by asymmetric division, which generates one daughter cell that is identical to the mother cell and a second daughter cell which has a separate fate. This notion of stem cell growth has recently been perturbed by the resurrection of an old theory, suggesting that stem cells are capable of cosegregating the old original template DNA strands in consecutive divisions so that the daughter cell that inherits the old DNA retains stem cell features while the daughter cell that acquires the new DNA enters the transit amplifying pool. If this hypothesis is correct, the number of mother stem cells may be genetically determined sometime early in life and cannot be expanded thereafter. Conversely, this class of "true" stem cells may decrease dramatically as a function of age and loss of CSCs may be a critical determinant of the development of the aging myopathy. Protection of the old DNA during stem cell division cannot prevent the consequences of oxidative stress and environmental factors commonly present with the course of life and myocardial aging, independently from disease processes. Excessive growth demands on CSCs may lead to their depletion and, as a consequence, to accumulation of senescent, poorly contracting, hypertrophied cardiomyocytes. Conversely, preservation of the pool of CSCs carrying the mother DNA may delay the manifestations of the senescent cardiac phenotype. Thus, the long-term objective of this application is to establish the role of endogenous CSCs in the development of the heart prenatally and postnatally, and their function in the fully mature organ and in the initiation and progression of the aging myopathy. PUBLIC HEALTH RELEVANCE: This research is directed to the documentation whether the entire lifespan of the heart from embryonic, fetal and postnatal development to adulthood and aging is regulated by the growth and differentiation of resident cardiac stem cells. Additionally, the possibility is raised that the loss of a pool of true stem cells that is genetically determined may condition myocardial aging and heart failure.

描述（由申请人提供）：认识到成体心肌中存在心脏干细胞 (CSC) 库，提出了以下问题：CSC 是否负责胚胎、胎儿和出生后心脏的心肌发生，调节成体器官中的心肌细胞更新并调理心肌老化。干细胞更新通过对称分裂发生，产生两个子干细胞，或通过不对称分裂发生，产生一个与母细胞相同的子细胞和一个具有不同命运的第二个子细胞。这种干细胞生长的概念最近因一个旧理论的复兴而受到干扰，该理论表明干细胞能够在连续分裂中共分离旧的原始模板DNA链，以便继承旧DNA的子细胞保留干细胞特征，而获得新DNA的子细胞进入转运放大池。如果这个假设是正确的，那么母体干细胞的数量可能在生命早期的某个时候就由基因决定，此后就无法扩增。相反，这类“真正的”干细胞可能会随着年龄的增长而急剧减少，CSC 的丧失可能是老年肌病发展的关键决定因素。干细胞分裂过程中旧DNA的保护不能防止氧化应激和环境因素的后果，这些因素通常存在于生命过程和心肌老化中，与疾病过程无关。对 CSC 的过度生长需求可能会导致其消耗，从而导致衰老、收缩不良、肥大的心肌细胞的积累。相反，保存携带母体 DNA 的 CSC 库可能会延迟衰老心脏表型的表现。因此，本申请的长期目标是确定内源性CSC在产前和产后心脏发育中的作用，以及它们在完全成熟的器官中以及在衰老肌病的发生和进展中的功能。公共健康相关性：本研究旨在记录心脏从胚胎、胎儿和出生后发育到成年和衰老的整个生命周期是否受到常驻心脏干细胞的生长和分化的调节。此外，由基因决定的真正干细胞库的丢失可能会导致心肌老化和心力衰竭。