Cardiac Stem Cells and Diabetic Cardiomyopathy

心脏干细胞和糖尿病心肌病

基本信息

批准号：
7845725
负责人：
JAN KAJSTURA
金额：
$ 29.5万
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：
2001
资助国家：
美国
起止时间：
2001-06-01 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7845725
关键词：
Ablation Affect Age Aging Antioxidants Apoptosis Apoptotic Architecture Attenuated Binding Biological Preservation Blood Vessels Cardiac Cardiac Death Cardiomyopathies Cell Aging Cell Death Cell Differentiation process Cell Membrane Permeability Cells Cessation of life Cicatrix Collagen Complex Coronary Vessels DNA DNA Damage DNA Double Strand Break DNA Single Strand Break DNA strand break Deposition Development Diabetes Mellitus Disease Dissociation Endothelial Cells Event Family Fibroblasts Functional disorder Funding Gene Targeting Generations Genes Genetic Genetic Transcription Growth Hand Heart Heart failure Heat shock proteins Homeostasis Hormones Hyperglycemia In Vitro Inflammatory Insulin-Dependent Diabetes Mellitus Intervention Lead Life Link Longevity MAPK14 gene Mammals Mediating Membrane Potentials Mitochondria Mus Muscle Cells Mutation Myocardial Myocardium Myopathy N-terminal Natural regeneration Necrosis Non-Insulin-Dependent Diabetes Mellitus Nuclear Oxidants Oxidative Stress Pathway interactions Pattern Performance Phenotype Phosphorylation Premature aging syndrome Principal Investigator Process Production Proteins Reaction Reactive Oxygen Species Renin Research Personnel Resistance Signal Transduction Smooth Muscle Myocytes Stem cells Structure Superoxide Dismutase TNFRSF5 gene TP53 gene Testing Time Toxic effect Tumor Suppressor Proteins Up-Regulation Ventricular Ventricular Remodeling Wild Type Mouse attenuation base biological adaptation to stress catalase cell age cytosolic receptor diabetic diabetic cardiomyopathy glycosylation improved injured mitochondrial membrane mitogen-activated protein kinase p38 overexpression p66(ShcA) protein premature prevent programs receptor receptor binding repaired senescence transcription factor

项目摘要

DESCRIPTION (provided by applicant): This application raises the possibility that diabetes is a disease process that negatively affects the pool of cardiac progenitor cells (CPCs) through the activation of the cell death pathway and inhibition of cell replication. Diabetes impairs the growth reserve of the heart, so that enhanced cardiac cell death cannot be counteracted by repopulating myocytes and vascular cells and the preservation of the architecture and function of the myocardium. The loss in cell turnover alters myocardial homeostasis and favors cellular senescence and death. Diabetes is associated with an increased formation of reactive oxygen species (ROS), and the amount of ROS and the age of the cells may determine whether the death signal triggers apoptosis or necrosis of myocytes, smooth muscle cells (SMCs) and endothelial cells (ECs). However, an efficient regeneration of myocytes, SMCs and ECs by differentiation of CPCs should replace the lost cells and preserve the integrity of the myocardium. Unfortunately, CPCs cannot escape the consequences of diabetes. Attrition of the pool of CPCs leads to insufficient replacement of old, dying cells, and the acquisition of the heart senescent phenotype. ROS condition distinct forms of cell death; low quantities promote apoptosis and high quantities induce cell necrosis. The potentiated production of ROS and cellular senescence with diabetes may result in a shift in the pattern of cell death from apoptosis to necrosis. The latter promotes an inflammatory reaction, fibroblast activation, and myocardial scarring. Thus, diabetic cardiomyopathy is viewed as a stem cell myopathy in which a defective stem cell compartment conditions aging and death of myocytes, and vascular SMCs and ECs. Targeted mutation of the p66shc gene increases the resistance to oxidative stress and prolongs life in mice. This constitutes the first demonstration that a gene can modify the formation and effects of ROS on survival and maximum lifespan in mammals. For this reason, p66shc-/- mice will be studied to test the hypothesis that oxidative stress, cellular aging, and mechanisms of cell death are the critical determinants of the diabetic heart. If this were correct, the impact of ROS on the heart should be attenuated in p66shc-/- mice, delaying the onset of a diabetic myopathy. Most importantly, we may be able to identify a genetic link between diabetes and ROS, on the one hand, and premature cellular senescence and heart failure, on the other.

描述（由申请人提供）：本申请提出了这样的可能性：糖尿病是一种通过激活细胞死亡途径和抑制细胞复制对心脏祖细胞（CPC）库产生负面影响的疾病过程。糖尿病会损害心脏的生长储备，因此无法通过心肌细胞和血管细胞的再生以及心肌结构和功能的保存来抵消心肌细胞死亡的增加。细胞更新的丧失会改变心肌稳态并有利于细胞衰老和死亡。糖尿病与活性氧 (ROS) 形成增加有关，ROS 的量和细胞的年龄可能决定死亡信号是否触发心肌细胞、平滑肌细胞 (SMC) 和内皮细胞 (EC) 的凋亡或坏死。）。然而，通过 CPC 的分化，心肌细胞、SMC 和 EC 的有效再生应该取代丢失的细胞并保持心肌的完整性。不幸的是，CPC 无法逃脱糖尿病的后果。 CPC 池的消耗导致老化、垂死细胞的替代不足，并导致心脏衰老表型的获得。 ROS 调节不同形式的细胞死亡；低量促进细胞凋亡，高量诱导细胞坏死。糖尿病引起的ROS产生增强和细胞衰老可能导致细胞死亡模式从细胞凋亡转变为坏死。后者促进炎症反应、成纤维细胞活化和心肌疤痕形成。因此，糖尿病心肌病被视为一种干细胞肌病，其中有缺陷的干细胞区室导致肌细胞、血管 SMC 和 EC 的衰老和死亡。 p66shc 基因的靶向突变可增强小鼠对氧化应激的抵抗力并延长寿命。这首次证明基因可以改变 ROS 的形成及其对哺乳动物生存和最长寿命的影响。因此，我们将对 p66shc-/- 小鼠进行研究，以检验氧化应激、细胞衰老和细胞死亡机制是糖尿病心脏的关键决定因素这一假设。如果这是正确的，那么 p66shc-/- 小鼠中 ROS 对心脏的影响应该会减弱，从而延缓糖尿病肌病的发作。最重要的是，我们或许能够一方面确定糖尿病和 ROS 之间的遗传联系，另一方面确定细胞过早衰老和心力衰竭之间的遗传联系。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Cardiac progenitor cells and biotinylated insulin-like growth factor-1 nanofibers improve endogenous and exogenous myocardial regeneration after infarction.

DOI：
10.1161/circulationaha.109.852285
发表时间：
2009-09-08
期刊：
Circulation
影响因子：
37.8
作者：
Padin-Iruegas ME;Misao Y;Davis ME;Segers VF;Esposito G;Tokunou T;Urbanek K;Hosoda T;Rota M;Anversa P;Leri A;Lee RT;Kajstura J
通讯作者：
Kajstura J