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Myofibril disassembly during neonatal heart muscle cell proliferation

新生儿心肌细胞增殖过程中的肌原纤维解体

基本信息

批准号：
8586349
负责人：
Bernhard Kuhn
金额：
$ 42.63万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-12-20 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8586349
关键词：
Affect Animal Model Birth Cardiac Cardiac Myocytes Cell Cycle Cell Proliferation Cell division Cell model Child Childhood Clinical Complication Congenital Abnormality Conserved Sequence Cytokinesis Cytoskeleton Data Development Gene Silencing Goals Heart Heart Transplantation Heart failure Human Immunofluorescence Microscopy In Vitro Infant Investigation MAPK14 gene Microscopy Mitogen-Activated Protein Kinase Kinases Mitogens Mitotic spindle Molecular Models Myocardial Myocardium Myofibrils Natural regeneration Neonatal Newborn Animals Patients Peptides Phase Problem Solving Process Proliferating Pump Regulation Reporter Research Role Sarcomeres Scientific Advances and Accomplishments Signal Transduction Structure Therapeutic Time Translations Video Microscopy Work age group base cardiac regeneration congenital heart disorder design extracellular heart function human MAPK14 protein improved in vivo inhibitor/antagonist innovation insight mitogen-activated protein kinase p38 molecular modeling nuclear division outcome forecast periostin receptor regenerative regenerative therapy time use two-photon

项目摘要

ABSTRACT Congenital heart disease, the most common birth defect, is frequently associated with deficient heart muscle, leading to heart failure. Currently, the only way to replace heart muscle cells, cardiomyocytes, is through heart transplantation. Regenerative therapies would transform the treatment of congenital heart disease and save many lives. We study the mechanisms of cardiomyocyte proliferation with the aim of increasing this process therapeutically. We have previously demonstrated that extracellular factors can be used to stimulate cardiomyocyte proliferation, leading to improved myocardial structure and function in animal models of heart failure. The clinical translation of this innovative approach requires understanding of how cardiomyocytes are able to perform two completely different tasks: contraction of myofibrils and cell division. We have shown that during cell division cardiomyocytes divide their contractile apparati, which consist of myofibrils, but the detailed mechanisms are not understood. It has been shown that myofibril formation and cardiomyocyte cytokinesis are controlled by mechanisms involving p38¿ mitogen-activated protein kinase (MAPK), but the role of p38¿ in myofibril disassembly remains unknown. Our preliminary data indicate that cardiomyocyte cell cycle activity in humans is highest in infants, suggesting that regenerative cardiomyocyte proliferation may be most effectively stimulated in this age group. We will therefore perform our investigations in neonatal animals. We hypothesize that myofibril disassembly in proliferating neonatal cardiomyocytes is a conserved, multi-step process that is controlled by a mechanism involving p38¿ MAPK and is associated with brief reduction of cardiomyocyte contractile function. In Aim 1 we will define and characterize the disassembly process. In Aim 2, we will modify p38 signaling and determine the effects on myofibril disassembly. In Aim 3, we will determine the effect of myofibril disassembly on cardiomyocyte function in the intact heart. The results of this research should increase the translational potential of regenerative strategies that stimulate cardiomyocyte proliferation.

摘要