Cardiac Stem Cell Growth, Aging and Death

心脏干细胞的生长、衰老和死亡

基本信息

批准号：
7233273
负责人：
JAN KAJSTURA
金额：
$ 36.98万
依托单位：
NEW YORK MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-04-01 至 2008-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7233273
关键词：
ABCB1 gene Actins Adult Affect Age Aging Aging-Related Process Angiotensin II Antigens Apoptosis Apoptotic Architecture Area Attenuated Behavior Binding Biology Blood Vessels Blood capillaries CD8B1 gene Canis familiaris Cardiac Cardiac Death Cardiac Myocytes Cardiac Myosins Cardiovascular system Caspase Cell Adhesion Molecules Cell Aging Cell Cycle Cell Death Cell Lineage Cell Nucleus Cell Proliferation Cells Cessation of life Characteristics Class Cleaved cell Commit Condition Connexin 43 Coronary Coronary Vessels Cytoplasm Cytoplasmic Protein DNA DNA Damage DNA Double Strand Break DNA strand break Desmin Development Differentiation and Growth Disease Down-Regulation Drops Dyes Elderly Endothelial Cells Evaluation Event Exhibits Factor VIII Failure Fibroblasts Functional disorder Generations Glial Fibrillary Acidic Protein Goals Growth Growth Factor Receptors Heart Heart Atrium Hematopoietic Hematopoietic stem cells Hepatocyte Growth Factor Human Hypertrophy In Vitro Injury Insulin-Like Growth Factor I Insulin-Like-Growth Factor I Receptor Locomotion Mammals Mediating Membrane Potentials Mitochondria Mus Muscle Cells Muscle Fibers Myocardial Myocardium Myogenin Myopathy Myosin Heavy Chains N-Cadherin Necrosis Neurons Nuclear Numbers Organ Oxidative Stress P-Glycoprotein P-Glycoproteins PECAM1 gene PTPRC gene Pathologic Pathway interactions Perfusion Permeability Pharmaceutical Preparations Phenotype Physiological Play Poison Population Process Property Protein p53 Proteins Proto-Oncogene Protein c-kit Rattus Reactive Oxygen Species Renin-Angiotensin System Research Personnel Resistance Role Scientist Signal Transduction Site Smooth Muscle Actin Staining Method Smooth Muscle Myocytes Stem cells Stimulus Structure Surface Surface Antigens System TNFRSF5 gene TP53 gene Terminology Time Tissues Undifferentiated Up-Regulation Ventricular age effect age related arteriole attenuation capillary caspase-3 caspase-9 cell age cell growth cell injury cell motility concept conditioning cytochrome c endonuclease extracellular in vivo inhibitor/antagonist injured migration mitochondrial membrane muscle enhancer factor-2A nestin protein neurofilament protein H novel oxidative DNA damage precursor cell primitive cell pro-apoptotic protein pro-caspase-3 progenitor programs receptor repaired response self-renewal senescence transcription factor

项目摘要

DESCRIPTION (provided by applicant): This project has three principal goals: 1. The recognition of the role that stem cell surface antigens have in conditioning the growth and differentiation of cardiac stem cells (CSCs) in myocardial cell lineages; 2. The demonstration that age leads to a downregulation of the hepatocyte growth factor (HGF)-cMet and insulin-like growth factor-1 (IGF-1)-IGF-1 receptor (IGF-1R) systems, and to an upregulation of the renin-angiotensin system (RAS) in CSCs and early committed cells; and 3. The identification of an age-dependent increase in the local RAS, which mediates the formation of reactive oxygen species (ROS), triggering apoptotic and necrotic death of CSCs, progenitors and precursors. Point 1 aims at the characterization of the classes of CSCs regulating the physiologic turnover of myocardial cells in the adult normal heart. This information is considered critical for the elucidation of the potential mechanisms of cardiac repair in disease states. Point 2 raises the possibility that attenuation of the HGF-c-Met system with age negatively interferes with the migration of CSCs from the storage areas to the injured sites of ventricular myocardium, limiting their activation and growth. Reduction of cell turnover results in accumulation of old cardiac cells with defective function. Similarly, the IGF-I-IGF-I R system might be downregulated in aging CSCs and this could affect cell replication, differentiation and survival, contributing to the development of the aging myopathy. Point 3 emphasizes the effects of oxidative damage induced by an upregulation of the local RAS not adequately counteracted by the IGF-I-IGF-1R system in the old heart. Low levels of oxidative challenge initiate apoptosis and high levels promote necrosis. Death of CSCs and early committed cells may result in the loss of the growth reserve of the aging myocardium. Senescent myocytes, coronary arterioles and capillary structures could die and the architecture of the ventricular wall may assume pathologic characteristics. These might include mural thinning, cavitary dilation, poor tissue perfusion, cardiac dysfunction and, ultimately, terminal failure and death. Thus, the hypothesis is advanced that CSC aging occurs and involves downregulation of growth factor receptor systems favoring locomotion, growth and differentiation. Conversely, inhibitors of the cell cycle and marker of cellular senescence increase in combination with oxidative DNA damage, potentiating the endogenous cell death pathway.

描述（由申请人提供）：该项目有三个主要目标： 1. 认识干细胞表面抗原在调节心肌细胞谱系中心脏干细胞（CSC）的生长和分化中的作用； 2. 证明年龄会导致肝细胞生长因子 (HGF)-cMet 和胰岛素样生长因子-1 (IGF-1)-IGF-1 受体 (IGF-1R) 系统的下调，并导致CSC 和早期定型细胞中的肾素-血管紧张素系统 (RAS)； 3. 确定局部 RAS 随年龄增长而增加，从而介导活性氧 (ROS) 的形成，引发 CSC、祖细胞和前体细胞的凋亡和坏死。第 1 点旨在描述调节成人正常心脏中心肌细胞生理更新的 CSC 类别。该信息被认为对于阐明疾病状态下心脏修复的潜在机制至关重要。第 2 点提出了一种可能性，即 HGF-c-Met 系统随着年龄的增长而减弱，会对 CSCs 从储存区域迁移到心室心肌损伤部位产生负面干扰，从而限制其激活和生长。细胞更新减少导致功能有缺陷的旧心肌细胞积聚。同样，IGF-I-IGF-I R 系统在衰老的 CSC 中可能会下调，这可能会影响细胞复制、分化和存活，从而导致衰老肌病的发展。第 3 点强调了老年心脏中局部 RAS 上调引起的氧化损伤的影响，而 IGF-I-IGF-1R 系统未能充分抵消这一影响。低水平的氧化挑战会引发细胞凋亡，高水平的氧化挑战会促进坏死。 CSC和早期定型细胞的死亡可能导致老化心肌失去生长储备。衰老的肌细胞、冠状动脉和毛细血管结构可能死亡，心室壁的结构可能呈现病理特征。这些可能包括壁变薄、空腔扩张、组织灌注不良、心脏功能障碍以及最终的晚期衰竭和死亡。因此，提出了这样的假设：CSC 老化的发生涉及有利于运动、生长和分化的生长因子受体系统的下调。相反，细胞周期抑制剂和细胞衰老标志物会随着氧化 DNA 损伤而增加，从而增强内源性细胞死亡途径。