Role of the cytoskeleton in cardiac regeneration

细胞骨架在心脏再生中的作用

基本信息

批准号：
8509019
负责人：
GLENN Lawrence RADICE
金额：
$ 18.45万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-15 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8509019
关键词：
Actins Adult Affect Amputation Animal Model Binding Bromodeoxyuridine Cardiac Cardiac Myocytes Cardiovascular Diseases Cell Cycle Cell Lineage Cell division Cytokinesis Cytoskeletal Modeling Cytoskeletal Proteins Cytoskeleton Erinaceidae Event Felis catus Genes Goals Grant Heart Heart failure Histone H3 In Vitro Injury Knock-out Knockout Mice Knowledge Label Location Mitotic Modeling Molecular Mus Myocardial Infarction Myocardium Myofibrils Natural regeneration Neuregulin 1 Patients Phenotype Process Proliferating Proteins Rattus Rodent Role Sarcomeres Signal Pathway Signal Transduction Source Staging Stem cells Stress Testing Tissues Transcription Coactivator Western World Zebrafish cardiac repair improved improved functioning in vivo inhibitor/antagonist injured innovation mouse model novel nuclear division postnatal programs regenerative repaired response rho smoothened signaling pathway therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Damage to the mammalian heart is considered irreversible due to the inability of cardiac progenitor cells and differentiated cardiomyocytes to effectively repopulate the injured myocardium. It is believed that myofibril and cytoskeleton organization of differentiated cardiomyocytes hinder their ability to undergo cell division. It was recently demonstrated that differentiated rat cardiomyocytes induced by neuregulin-1 disassemble their sarcomeres in the midzone during karyokinesis and cytokinesis. A similar process has been shown to occur in adult zebrafish during heart regeneration after amputation. Alterations in sarcomeric proteins and cytoskeleton in injured heart suggest dedifferentiation of adult cardiomyocytes requires a transient reorganization of the cytoskeleton. However, the molecular mechanism(s) responsible for cytoskeleton remodeling in postnatal cardiomyocytes remain poorly understood. In this exploratory R21 application, we will directly investigate this mechanism by inducing deletion of the cytoskeletal regulator proteins, ¿-catenins in the mouse heart. We provide evidence that adult cardiomyocytes reenter the cell cycle and undergo cytokinesis in the absence of ¿-catenins. We hypothesize that loss of ¿-catenins leads to cytoskeletal changes permissive for cell cycle reentry and cytokinesis of differentiated cardiomyocytes, thus representing a novel mechanism for cardiac regeneration. The following interrelated aims are proposed: (1) To define signal pathways that promote cardiomyocyte regeneration in a cardiac specific ¿-catenin double knockout (DKO) model. In vivo and in vitro approaches will be used to examine the effects of specific signaling pathways on cardiomyocyte proliferation in the absence of ¿-catenins. (2) To assess the de-differentiation of adult cardiomyocytes in the ¿-catenin DKO heart. Cell lineage tracing will be performed to determine the cellular source of the increased cardiomyocytes in the ¿-catenin DKO heart. (3) To determine the response of ¿-catenin DKO mice to myocardial infarction. We will examine the cellular, molecular, and functional consequences that occur after myocardial infarction in the ¿-catenin DKO compared with their littermate controls. We hypothesize that deletion of ¿-catenins will promote cardiomyocyte proliferation leading to enhanced repair of damaged tissue, thus improving cardiac function after injury. The long term goal of this exploratory R21 proposal is to determine if interfering with the cytoskeletal proteins, ¿-catenins, represents a potential therapy to enhance cardiac repair in heart failure patients.

描述（由申请人提供）：由于心脏祖细胞和分化的心肌细胞无法有效地重新填充受损的心肌，因此对哺乳动物心脏的损伤被认为是不可逆的。据信，分化的心肌细胞的肌原纤维和细胞骨架组织阻碍了它们接受细胞的能力。是的。最近证明，神经调节蛋白-1 诱导的分化大鼠心肌细胞在核分裂和胞质分裂过程中会分解其中部的肌节，在成年斑马鱼截肢后的心脏再生过程中也会发生类似的过程。受损心脏中肌节蛋白和细胞骨架的改变表明了去分化。成年心肌细胞的生长需要细胞骨架的短暂重组，然而，负责细胞骨架的分子机制。出生后心肌细胞的重塑仍然知之甚少，在这个探索性的 R21 应用中，我们将通过诱导细胞骨架调节蛋白的缺失来直接研究这种机制。我们提供了小鼠心脏中的连环蛋白的证据，表明成年心肌细胞在没有 ¿ 的情况下重新进入细胞周期并经历胞质分裂。 -连环蛋白。 -连环蛋白导致细胞骨架变化，允许细胞周期重入和分化心肌细胞的胞质分裂，从而代表了心脏再生的新机制。提出了以下相互关联的目标：（1）定义促进心脏特异性心肌细胞再生的信号通路。 -连环蛋白双敲除（DKO）模型将用于检查特定信号通路在缺乏 ¿ 的情况下对心肌细胞增殖的影响。 -连环蛋白 (2) 评估 ¿ 中成体心肌细胞的去分化。 -连环蛋白 DKO 心脏将进行细胞谱系追踪以确定 ¿ -连环蛋白 DKO 心脏 (3) 确定 ¿ 的反应。 -连环蛋白 DKO 小鼠对心肌梗塞的影响我们将研究心肌梗塞后发生的细胞、分子和功能后果。 -连环蛋白 DKO 与同窝对照相比，我们勇敢地删除了 ¿ -连环蛋白将促进心肌细胞增殖，从而增强受损组织的修复，从而改善损伤后的心脏功能。该探索性 R21 提案的长期目标是确定是否干扰细胞骨架蛋白，¿ -连环蛋白，代表一种潜在的疗法增强心力衰竭患者的心脏修复能力。