ARRHYTHMOGENIC REMODELING IN HUMAN HEART FAILURE

人心力衰竭中的心律失常性重塑

基本信息

批准号：
8702227
负责人：
IGOR R EFIMOV
金额：
$ 49.63万
依托单位：
WASHINGTON 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：
2012-08-15 至 2015-01-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8702227
关键词：
Action Potentials Adherens Junction Adrenergic Agents American Anatomy Angiotensins Animal Model Animals Anisotropy Arrhythmia Biomedical Research Calcium Canis familiaris Cardiac Cardiomyopathies Cavia Cell Line Cells Clinical Clinical Trials Communities Coupling Data Disease Employee Strikes Etiology Failure Functional disorder Gap Junctions Genes Gifts Heart Heart Transplantation Heart failure Heterogeneity Homo sapiens Human In Vitro Investigation Ion Channel Knowledge Laboratories Lead Life Link Maps Mediating Mediator of activation protein Methodology Modeling Molecular Molecular Biology Techniques Molecular Genetics Morbidity - disease rate Mus Myocardium Na(+)-K(+)-Exchanging ATPase Operative Surgical Procedures Optics Organ Oryctolagus cuniculus Pathologic Pathologic Processes Patients Physiological Physiology Preparation Proteins Pump Rattus Research Safety Signal Transduction Stress Sudden Death Symptoms Testing Therapeutic Tissue Donors Tissues Translational Research Translations Transplantation Treatment Efficacy Validation Ventricular adrenergic base biophysical properties heart rhythm implantable device mortality programs receptor sudden cardiac death therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Heart failure (HF) is the leading cause of mortality and morbidity, which afflicts 5.7 million Americans. HF management includes surgery, implantable device and pharmacological therapy targeting angiotensin and adrenergic signaling. Numerous animal models of heart failure have been generated and studied for decades in effort to identify therapeutic targets for treatment of human HF patients. However, it is becoming increasingly evident that this strategy has yielded limited therapeutic options for the treatment o HF. Significant genetic, molecular, cellular, anatomical, and systemic differences among species are likely to be responsible for failure of translation from cell lines and animal models t humans. Cardiac rhythm disorders are striking examples of such translational failure. Despite deep knowledge of the biophysical properties of numerous ion channels, pumps, and exchangers gained over half a century of research conducted at huge expense, current pharmacological therapies used to treat arrhythmias are nonspecific and often ineffective. The main reason for this failure is the complexity of human cardiac physiology at the molecular, cellular and tissue levels. It is paradoxical, but we know much more about ion channels and action potentials in the mouse, rat, guinea pig, rabbit, and canine as compared to our own species - Homo sapiens. We have recently developed a program, which allows investigation of the mechanisms of arrhythmogenic remodeling in live human hearts in vitro. In this project we will investigate a number of mechanistic hypothesis linking HF and arrhythmia in live cardiac tissue from donors and patients with HF. In summary, we will develop, refine and extend experimental methodology, which is currently applied only to animal cardiac preparations in basic physiology laboratories, to deepen our understanding of human cardiac pathophysiology. This approach will modify and enhance the currently dominant translational paradigm and provide new important directions of research, which will stimulate and reinvigorate a biomedical research community that has ignored human physiology and thus delayed effective translation of needed therapies for HF and sudden cardiac death.

描述（由申请人提供）：心力衰竭（HF）是死亡率和发病率的主要原因，折磨了570万美国人。 HF管理包括手术，可植入的装置和靶向血管紧张素和肾上腺素能信号的药理治疗。数十年来，已经生成并研究了许多心力衰竭的动物模型，以识别治疗人类HF患者的治疗靶标。但是，越来越明显的是，该策略为治疗方法提供了有限的治疗选择。物种之间的显着遗传，分子，细胞，解剖学和全身差异可能是导致细胞系和动物模型的翻译失败。心律障碍是这种转化失败的引人注目的例子。尽管对众多离子通道，泵和交换器的生物物理特性有深入了解，但在半个多世纪的研究中以巨大的费用进行了研究，但目前用于治疗心律失常的药理疗法是非特异性的，而且通常是无效的。这种失败的主要原因是在分子，细胞和组织水平上人类心脏生理的复杂性。它是自相矛盾的，但我们对小鼠，大鼠，豚鼠，兔子和犬的离子通道和动作电位的了解更多，与我们自己的物种 - 智人相比。我们最近开发了一个程序，该程序允许研究体外活体心脏中心律失常重塑的机制。在这个项目中，我们将研究许多机械假设，这些假设将捐赠者和HF患者的活心脏组织中的HF和心律不齐联系起来。总而言之，我们将开发，完善和扩展实验方法，目前仅适用于基本生理实验室中的动物心脏制剂，以加深我们对人类心脏病生理学的理解。这种方法将修改和增强当前主要的翻译范式，并提供新的重要研究方向，这将刺激和振兴一个忽略人类生理学的生物医学研究界，从而延迟了对HF所需疗法的有效翻译和猝死。