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Stem Cells in the Developing Heart

发育中的心脏中的干细胞

基本信息

批准号：
8452203
负责人：
Marcello Rota
金额：
$ 39.8万
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：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8452203
关键词：
1,2-diacylglycerol Abbreviations Actinin Actins Address Adult Affect Age Angiotensin II Anterior Antigens Biological Models Birth Calcium Calcium Channel Calcium Oscillations Calcium-Sensing Receptors Cardiac Cardiac Myocytes Cardiovascular Diseases Cell Differentiation process Cell Proliferation Cell division Cell physiology Cells Cellular Structures Complement Connexin 43 Contractile Proteins Coupled Data Development Differentiation and Growth Diglycerides Discrimination Elements Embryo Embryonic Heart Endoplasmic Reticulum Equation Event Fluorescence Gap Junctions Generations Goals Growth Heart Heart Atrium Homeostasis Human Hypertrophy ITPR1 gene In Vitro Inositol Insulin-Like Growth Factor I Laboratories Lead Life Mechanics Mediating Mesoderm Methodology Mitotic Mitotic spindle Modeling Morphogenesis Mus Muscle Cells Muscle Contraction Myocardial Myosin Heavy Chains Organ Pattern Peptidyl-Dipeptidase A Phenotype Physiological Population Process Proliferating Property Proteins Proto-Oncogene Protein c-kit Published Comment Renin-Angiotensin System Research Role Ryanodine Receptor Calcium Release Channel Sarcoplasmic Reticulum Scheme Spatial Distribution Staging Stem cells Stretching System Time Transgenic Mice Ventricular Work Workload abstracting attenuation base calcium metabolism cell growth design fetal immunocytochemistry in vivo mechanical behavior migration mouse model postnatal prenatal primitive cell progenitor promoter receptor regenerative repaired response transcription factor tripolyphosphate young adult

项目摘要

06. Project Summary/Abstract This application raises the possibility that the myocyte compartment of the embryonic, fetal and post-natal heart is generated by activation and lineage commitment of a pool of resident c-kit-positive cardiac progenitor cells (CPCs) which are clustered in niches within the primitive heart. Cardiac morphogenesis may be mediated by spontaneous calcium oscillations within CPCs which lead to cell growth and the acquisition of the myocyte phenotype. The possibility is raised that the fate of CPCs is regulated by transient changes in intracellular calcium which constitute the essential element of symmetric and asymmetric division of these primitive cells. Similarly, calcium oscillations condition the differentiation of CPCs into functionally competent myocytes which become electrically and mechanically excitable. To address these fundamental issues, two transgenic mouse models have been developed: one in which EGFP is under the control of the c-kit-promoter (c-kit-EGFP mouse) and the second in which EGFP expression is regulated by the cardiac specific ¿-myosin heavy chain promoter (¿MHC-EGFP mouse). The c-kit-EGFP mouse should allow us to identify the embryonic stages at which c-kit-positive-EGFP-positive CPCs appear in the forming heart, their anatomical distribution and developmental changes in prenatal and postnatal life. The ¿MHC-EGFP mouse will permit us to define the localization and spatial distribution of forming myocytes postnatally and this information will be complemented with the data to be obtained in the c-kit-EGFP mouse. With these two models, the relationship between the generation of myocytes and the activation, commitment and differentiation of CPCs will be established. These studies will be integrated with the analysis of the electrophysiological, mechanical and calcium handling properties of CPCs and linearly related cells together with their pattern of growth and differentiation. Ultimately, the interdependence of cellular physiology and growth with calcium being the master regulatory system will be determined. Therefore, the role that intracardiac progenitor cells have in the developing heart will be characterized and this information may have important implications in the myocardial adaptations to ischemic and non-ischemic damage later in life.

06.项目总结/摘要这一应用提出了胚胎、胎儿和出生后的心肌细胞区室通过激活和谱系定型一群常驻c-kit阳性心脏祖细胞产生心脏细胞（CPC）聚集在原始心脏内的壁龛中。心脏形态发生可能是由通过CPC内的自发钙振荡，导致细胞生长和肌细胞的获得，表型提出了这样的可能性，即CPC的命运是由细胞内的瞬时变化调节的。钙是构成这些原始细胞对称和不对称分裂的基本元素。类似地，钙振荡调节CPC分化为功能上有能力的肌细胞，变得电和机械可激发。为了解决这些基本问题，两个转基因小鼠已经开发了模型：其中EGFP在c-kit启动子的控制下（c-kit-EGFP 第二种是EGFP的表达受心脏特异性肌球蛋白重链的调节启动子（MHC-EGFP小鼠）。c-kit-EGFP小鼠应该可以让我们识别胚胎阶段，哪些c-kit阳性-EGFP阳性CPC出现在形成的心脏中，它们的解剖学分布和出生前和出生后的发育变化。MHC-EGFP小鼠将允许我们定义出生后形成的心肌细胞的定位和空间分布，这些信息将得到补充在c-kit-EGFP小鼠中获得的数据。有了这两个模型，将建立肌细胞的产生和CPC的活化、定型和分化。这些研究将与电生理、机械和钙处理的分析相结合 CPC和线性相关细胞的性质以及它们的生长和分化模式。最后，细胞生理学和生长与钙的相互依赖性是主要的调节系统，测定因此，心内祖细胞在发育中的心脏中的作用将是这些信息可能对心肌对缺血的适应有重要意义。和非缺血性损伤。