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Promoting Cardiomyocyte Cell Cycle Activity and Cardiac Regeneration through IL13 Signaling

通过 IL13 信号传导促进心肌细胞周期活性和心脏再生

基本信息

批准号：
9907028
负责人：
Samantha J Paddock
金额：
$ 4.55万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9907028
关键词：
Address Adolescent Adult Anti-Inflammatory Agents Bromodeoxyuridine Cardiac Cardiac Myocytes Cell Cycle Collection Complex DNA biosynthesis Data Echocardiography Event Exhibits Fibrosis Goals Heart Heart Injuries Heart failure Histologic Histology Human Hypertrophy IL13RA1 gene Impairment In Vitro Infarction Injections Injury Interleukin 4 Receptor Interleukin-13 Knock-out Knockout Mice Label Lead Life Lower Organism MAPK3 gene Measures Mediating Modeling Mus Myocardial Infarction Myocardium Natural regeneration Neonatal Operative Surgical Procedures Outcome Patients Persons Phenotype Phosphorylation Physiological Proliferating Proteins Proto-Oncogene Proteins c-akt RNA Rattus Recombinant Interleukin-13 Recovery Role Signal Pathway Signal Transduction Small Interfering RNA Testing Tissues Translating Trichrome stain method United States Vertebrates Work blood pump cardiac regeneration cardiogenesis coronary fibrosis cost cytokine experimental study functional loss functional restoration heart function improved in vivo knock-down mouse model neonatal injury neonate novel receptor regenerative repaired subcutaneous virtual

项目摘要

Title: Promoting Cardiomyocyte Cell Cycle Activity and Cardiac Regeneration through IL13 Signaling Project Summary Close to 6 million people in the United States have heart failure (HF), which costs the nation an estimated $30.7 billion each year. HF occurs when the heart has a reduced ability to pump blood which is usually caused by diminished contractility of the myocardium. Studying cardiac regeneration in lower vertebrates provides a unique opportunity to elucidate pro-regenerative mechanisms to restore function in the heart. Interestingly, the neonatal mouse contains the ability to regenerate myocardium during its first week of life. Previous work uncovered a role for Interleukin 13 (IL13) in directly stimulating cardiomyocyte cell cycle activity and neonatal cardiac regeneration in the mouse. IL13 signals through the IL4Ra/IL13Ra1 heterodimer receptor, which is present on cardiomyocytes through adulthood. Preliminary experiments looking at the knockout of IL4Ra indicate diminished cell cycle activity and lack of cardiac regeneration when compared to wildtype littermate controls. Additionally, DNA synthesis and MI recovery were improved in 7-day old, non-regenerative mice when administered exogenous IL13. Overall, this proposal addresses the hypothesis that IL13 signaling enhances cardiomyocyte cell cycle activity and promotes cardiac regeneration in neonatal and adult mice. The following proposed experiments will investigate the cardio-regenerative potential of IL13 signaling both endogenously and exogenously. Specific Aim 1 will test the hypothesis that IL4Ra/IL13Ra1 depletion on cardiomyocytes will inhibit cell cycle activity and cardiac regeneration. Both in vitro and in vivo experiments will assess the endogenous role of IL13 directly on cardiomyocytes. The in vivo experiments will examine regenerative potential in a novel mouse model (IL4Rafl/fl Myh6CRE) which have a cardiomyocyte-specific depletion of IL4Ra. Aim 2 will address the hypothesis that exogenous administration of IL13 will promote cardiac regeneration and cell cycle activity in adult mice. Myocardial infarctions will be induced in 8-10 week old mice, followed by daily administration of recombinant IL13 for 4 weeks. Upon collection, cardiac function and proliferative potential will be analyzed through histology, qPCR, BrdU/EdU incorporation, and echocardiography.

标题：通过IL 13信号通路促进心肌细胞周期活性和心脏再生项目摘要在美国，近600万人患有心力衰竭（HF），据估计，每年307亿美元。当心脏泵血能力降低时，HF就会发生，心肌收缩力减弱研究低等脊椎动物的心脏再生，独特的机会，阐明促再生机制，以恢复心脏功能。有趣的是新生小鼠在其生命的第一周内具有再生心肌的能力。以前的工作揭示了白细胞介素13（IL 13）在直接刺激心肌细胞细胞周期活性和新生儿小鼠心脏再生。IL 13通过IL 4 Ra/IL 13 Ra 1异二聚体受体发出信号，存在于成年期的心肌细胞上。研究IL 4 Ra敲除的初步实验表明与野生型同窝仔相比细胞周期活性降低和缺乏心脏再生对照此外，在7日龄非再生小鼠中，DNA合成和MI恢复得到改善当施用外源性IL 13时。总的来说，该提议解决了IL 13信号转导增强心肌细胞周期活性，促进新生儿和成人心脏再生小鼠以下提出的实验将研究IL 13信号传导的心脏再生潜力既有内生的也有外生的。特异性目的1将检验IL 4 Ra/IL 13 Ra 1耗竭在心肌细胞会抑制细胞周期活动和心脏再生。体外和体内实验都将评估IL 13直接对心肌细胞的内源性作用。体内实验将检查在具有心肌细胞特异性的新的小鼠模型（IL 4 Rafl/fl Myh 6CRE）中的再生潜力 IL 4 Ra的缺失。目的2将阐述外源性施用IL 13将促进IL 13表达的假设。心脏再生和细胞周期活性。8-10周后诱发心肌梗死老年小鼠，随后每日施用重组IL 13，持续4周。采集时，心脏功能将通过组织学、qPCR、BrdU/EdU掺入和超声心动图