Improving Cardiac Function After Myocardial Infarction

改善心肌梗塞后的心脏功能

基本信息

批准号：
9020987
负责人：
Steven R Houser
金额：
$ 229.36万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
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：
2012-05-07 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9020987
关键词：
Adrenergic Agents Animal Experiments Animal Model Animals Cardiac Cardiac Death Cardiac Myocytes Cell Death Cells Cessation of life Characteristics Congestive Heart Failure Depressed mood Disease Ensure Evaluation Family suidae Genes Goals Health Heart Heart Abnormalities Housing Human Hypertrophy Inflammation Lead Modeling Muscle Cells Myocardial Infarction Myocardial Ischemia Myocardial dysfunction Natural regeneration PRKCA gene Pathologic Processes Patients Procedures Process Program Research Project Grants Property Pump Regulation Research Personnel Research Project Grants Resources Rodent Model Science Signal Transduction Signaling Molecule Staging Stress Structure Testing Therapeutic Therapeutic Intervention Tissues Translating Translations cardiac repair data sharing effective therapy experience functional disability functional loss functional restoration improved new therapeutic target novel novel strategies novel therapeutics premature prevent programs research study vector

项目摘要

DESCRIPTION (provided by applicant): The goal of this program project grant is to develop novel approaches to prevent, slow or reverse the pathological structural and functional cardiac remodeling that takes place after a myocardial infarction (Ml). Ischemic heart disease is a major health problem with few effective therapies. Ml usually leads to congestive heart failure with premature death or severe functional disability. While many cardiac defects have been identified in the diseased heart, very few have been translated into novel therapies. The objective of this PPG is to define novel mechanisms of cardiac dysfunction after Ml and to test, in large animal models, novel approaches to block these pathological processes so that cardiac function is improved. The program involves 3 projects and 4 supportive cores. All project leaders are established investigators and they have all collaborated extensively over the past decade. Project 1 (Houser) will explore the idea that blocking excess Ca entry into microdomains that house pathological signaling molecules will reduce cardiac dysfunction and death after Ml. Project 2 (Molkentin) will determine if reducing the activity of PKC-alpha will promote increased myocyte contractility and reduce cell death. Project 3 (Koch) will interrupt abnormally activated adrenergic signaling cascades that lead to cell death and reduce new myocyte formation. Discovery experiments to define and validate those processes we hope to modify to improve post Ml structure and function will be done in small animal models. Final tests of developed therapeutic approaches will be done in a large animal model with structural and functional characteristics that are similar to those in humans, setting the stage for rapid translation of novel therapies to patients with ischemic heart disease. The 3 projects are supported by 4 cores. A large animal model (pig) core will perform all Ml procedures and cardiac evaluations. This core will also perform all therapeutic interventions. A cell and tissue core will perform small animal experiments and will evaluate the properties of cells and tissues from all animal studies. A gene vector core will generate AAV6 vectors with novel therapeutics for testing in the pig Ml model. An administrative core will ensure data sharing and effective use of all resources.

描述（由申请人提供）：该计划项目授予的目标是开发新的方法，以防止，减慢或扭转心肌梗死（ML）后发生的病理结构和功能性心脏重塑。缺血性心脏病是很少有效疗法的主要健康问题。 ML通常会导致充血性心力衰竭，过早死亡或严重的功能障碍。尽管已经在患病的心脏中发现了许多心脏缺陷，但很少有人被转化为新型疗法。该PPG的目的是定义ML后心脏功能障碍的新型机制，并在大型动物模型中测试了阻断这些病理过程的新方法，从而改善了心脏功能。该计划涉及3个项目和4个支持核心。所有项目负责人都是成立的调查人员，他们在过去十年中都进行了广泛的合作。项目1（Houser）将探讨以下想法：将过量的CA进入微区域，即房屋病理信号分子将减少ML后心脏功能障碍和死亡。项目2（Molkentin）将确定减少PKC-Alpha活性是否会促进肌细胞收缩力增加并减少细胞死亡。项目3（KOCH）将中断异常激活的肾上腺素能信号传导级联反应，从而导致细胞死亡并减少新的肌细胞形成。发现和验证我们希望修改的这些过程以改善ML结构和功能的发现实验将在小动物模型中进行。开发的治疗方法的最终测试将在具有与人类相似的结构和功能特征的大型动物模型中进行，这为新型疗法快速转化为缺血性心脏病患者奠定了基础。这三个项目得到了4个核心的支持。大型动物模型（PIG）核心将执行所有ML程序和心脏评估。该核心还将执行所有治疗性干预措施。细胞和组织核心将进行小动物实验，并将评估所有动物研究中细胞和组织的特性。基因载体核心将在猪ML模型中生成具有用于测试的新型疗法的AAV6载体。管理核心将确保数据共享和有效利用所有资源。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Molecular networks underlying myofibroblast fate and fibrosis.

DOI：
10.1016/j.yjmcc.2016.05.002
发表时间：
2016-08
期刊：
Journal of molecular and cellular cardiology
影响因子：
5
作者：
Stempien-Otero A;Kim DH;Davis J
通讯作者：
Davis J

Protein Kinase C Inhibition With Ruboxistaurin Increases Contractility and Reduces Heart Size in a Swine Model of Heart Failure With Reduced Ejection Fraction.

使用 Ruboxistaurin 抑制蛋白激酶 C 可增加心力衰竭猪模型的收缩性并减小心脏大小，并减少射血分数。

DOI：
10.1016/j.jacbts.2017.06.007
发表时间：
2017
期刊：
JACC. Basic to translational science
影响因子：
0
作者：
Sharp3rd,ThomasE;Kubo,Hajime;Berretta,RemusM;Starosta,Timothy;Wallner,Markus;Schena,GianaJ;Hobby,AlexanderR;Yu,Daohai;Trappanese,DanielleM;George,JonC;Molkentin,JefferyD;Houser,StevenR
通讯作者：
Houser,StevenR