The Mechanistic Basis of Cyclin A2-Mediated Cardiac Repair

细胞周期蛋白 A2 介导的心脏修复的机制基础

基本信息

批准号：
7244968
负责人：
Hina W Chaudhry
金额：
$ 39.03万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-15 至 2008-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7244968
关键词：
Adenoviruses Adult Arts Biomedical Engineering Bone Marrow Bromodeoxyuridine Cardiac Cardiac Myocytes Cardiac Output Cardiology Cardiovascular Diseases Cell Cycle Cell Cycle Arrest Cell Proliferation Cell Transplantation Cells Cellular biology Characteristics Cicatrix Clinical Coculture Techniques Complementary DNA Cyclin-Dependent Kinases Cyclins Cytokinesis Developmental Biology Embryo Engineering Exhibits Gene Transfer Genetic Heart Heart failure In Vitro Infarction Injection of therapeutic agent Injury Investigation Life Magnetic Resonance Imaging Mammalian Cell Measures Mediating Mitosis Mitotic Modeling Monitor Mus Muscle Cells Myocardial Infarction Myocardium Myosin Heavy Chains Natural regeneration Neonatal Newts Operative Surgical Procedures Organogenesis Personal Satisfaction Play Population Proliferating Radiology Specialty Rattus Recovery Reporter Genes Research Personnel Research Training Resources Role Side Silicon Dioxide Site Source Stem cells Techniques Testing Therapeutic Time Tissue Engineering Tissues Transgenic Mice Transgenic Organisms Translations Transplantation Ventricular Cardiac alpha-Myosin Video Microscopy Viral base cell dedifferentiation cell type concept cyclin A2 day in vivo insight interdisciplinary approach mouse model novel postnatal progenitor programs promoter repaired response response to injury tool uptake

项目摘要

DESCRIPTION (provided by applicant): The concept of stimulating cardiomyocyte mitotic divisions has dramatic implications for cardiac regeneration and hence, cardiovascular disease. We previously demonstrated for the first time that mammalian cardiomyocyte mitoses can occur postnatally if cyclin A2 is constitutively expressed in cardiomyocytes in a transgenic mouse model. Our more recent results demonstrate that cyclin A2 mediates cardiomyocyte mitoses in the transgenic hearts after myocardial infarction (Ml) is induced, thus repairing the heart with significant recovery of cardiac function when compared with nontransgenic littermate controls. To explore potential clinical translation of these results, we administered cDNA encoding cyclin A2 via de-activated adenovirus to infarcted rats and noted that the rats receiving adeno-cyclin A2 undergo cellular regeneration at the sites of injection and have preserved cardiac output when compared to controls which received empty adenovirus. We hypothesize that there are two potential mechanisms mediating the regeneration we have observed. First, side population (SP) stem cells appear to differentiate into cardiomyocytes in our mouse infarction model, but mitoses in these immature cardiomyocytes are only noted in the transgenic mice, thus possibly uncovering a novel mechanism to induce hyperproliferative progenitor cells. Second, we note a significant increase in expression of phosphohistone H3 and uptake of BrdU in the peri-infarct zone of transgenic mice compared to nontransgenic controls, implicating dedifferentiation and division of adult cardiomyocytes. Utilizing SP cells from transgenic and nontransgenic mice, we propose to explore the first mechanism via in vitro studies of proliferation of SP cell-derived progenitor cells and in vivo studies of SP cell transplantation into a mouse infarction model. Additionally, we will use novel engineered cardiac tissues to evaluate both mechanisms by testing the response to injury of both SP cell-derived progenitors and adult cardiomyocytes from transgenic and nontransgenic mice. The second mechanism will also be examined using viral transfer of cyclin A2 cDNA into adult cardiomyocytes in vitro and the utilization of video microscopy to monitor mitosis and cytokinesis of these cells. These studies are proposed in order to elucidate a more directed path to clinical therapy.

描述（由申请人提供）：刺激心肌细胞有丝分裂分裂的概念对心脏再生具有巨大的影响，因此是心血管疾病。我们先前首次证明，如果在转基因小鼠模型中在心肌细胞中组成性表达细胞周期蛋白A2，则在产后发生哺乳动物心肌细胞有丝分裂。我们最近的结果表明，在诱导心肌梗死（ML）后，细胞周期蛋白A2介导了转基因心脏中的心肌细胞有丝质，因此与非转基因窝窝对照相比，在心脏上恢复了心脏，并显着恢复心脏功能。为了探索这些结果的潜在临床翻译，我们通过去激活的腺病毒来施用编码细胞周期蛋白A2的cDNA到梗塞的大鼠，并指出，与接收空腺病毒相比，接受腺癌A2 A2 A2的大鼠会在伤害部门进行细胞再生并保留了与对照相比，并保留了受伤的心脏输出。我们假设有两个潜在的机制介导了我们观察到的再生。首先，在我们的小鼠梗塞模型中，侧群（SP）干细胞似乎分化为心肌细胞，但是这些未成熟的心肌细胞中只有在转基因小鼠中注意到有丝分裂，因此可能会发现一种新型机制来诱导高增殖性祖细胞。其次，我们注意到，与非转基因对照相比，转基因小鼠的磷酸组酮H3表达显着增加和BRDU在转基因小鼠周围的摄取，这暗示了成人心肌细胞的去分化和分裂。利用转基因和非转基因小鼠的SP细胞，我们建议通过体外研究SP细胞衍生的祖细胞的增殖以及SP细胞移植到小鼠梗塞模型中的体内研究。此外，我们将使用新型的工程心脏组织来评估这两种机制，通过测试对SP细胞衍生的祖细胞和来自转基因和非转基因小鼠的损伤的反应。还将使用细胞周期蛋白A2 cDNA的病毒转移到体外的成年心肌细胞中，并利用视频显微镜来监测这些细胞的有丝分裂和细胞因子。提出了这些研究，以阐明更有方向的临床治疗途径。