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）：此申请提高了糖尿病是一种疾病过程，通过激活细胞死亡途径和抑制细胞复制对心脏祖细胞（CPC）产生负面影响。糖尿病会损害心脏的生长储备，因此无法通过重生心肌和血管细胞来抵消心脏细胞死亡的增强，并保留心肌的结构和功能。细胞更新的损失改变了心肌稳态，并有利于细胞衰老和死亡。糖尿病与活性氧（ROS）的形成增加有关，ROS的量和细胞的年龄可能决定死亡信号是否触发肌细胞的凋亡或平滑肌细胞（SMC）和内皮细胞（ECS）的凋亡或坏死。但是，通过分化CPC的肌细胞，SMC和EC的有效再生应取代丢失的细胞并保留心肌的完整性。不幸的是，CPC无法逃脱糖尿病的后果。 CPC池的损耗导致旧，垂死的细胞的替代不足以及心脏衰老表型的获得。 ROS条件不同的细胞死亡形式；低量会促进凋亡和大量诱导细胞坏死。糖尿病的ROS和细胞衰老的增强产生可能导致细胞死亡的模式从细胞凋亡转变为坏死。后者促进了炎症反应，成纤维细胞激活和心肌疤痕。因此，糖尿病性心肌病被视为干细胞肌病，其中干细胞区室衰老和肌细胞死亡，血管SMC和ECS的死亡。 p66SHC基因的靶向突变增加了对氧化应激的耐药性，并延长了小鼠的寿命。这构成了第一个证明，即基因可以改变ROS对哺乳动物中生存和最大寿命的形成和影响。因此，将研究P66SHC - / - 小鼠，以检验以下假设：氧化应激，细胞衰老和细胞死亡的机制是糖尿病心脏的关键决定因素。如果这是正确的，则应在p66SHC - / - 小鼠中减弱ROS对心脏的影响，从而延迟糖尿病性肌病的发作。最重要的是，另一方面，我们可能能够鉴定糖尿病和ROS之间的遗传联系，另一方面是过早的细胞衰老和心力衰竭。

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