Translational Study of Cardiac Dysfunction

心脏功能障碍的转化研究

基本信息

批准号：
9013490
负责人：
Nipavan Chiamvimonvat
金额：
$ 38.5万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-02-01 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9013490
关键词：
Acids Address Anti-Inflammatory Agents Anti-inflammatory Apoptosis Arrhythmia Atrial Fibrillation Biological Biological Assay Cardiac Cardiac Myocytes Cardiovascular Diseases Cells Chest Clinical Cytochrome P450 Development Disease Disease model Enzymes Epoxide hydrolase Experimental Designs Fibroblasts Fibrosis Figs - dietary Functional disorder Funding Health Heart Heart Atrium Heart Diseases Heart Hypertrophy Heart failure Hypertrophy In Vitro Inflammatory Laboratories Malignant - descriptor Maps Modeling Morbidity - disease rate Muscle Cells Mutation Myocardial Infarction Myocardial dysfunction NF-kappa B Optics Outcome Pathway interactions Play Population Prevention Production Proteins Risk Role Stimulus Stress Techniques Testing Therapeutic Time United States Ventricular Ventricular Arrhythmia Ventricular Remodeling base chemokine clinically relevant coronary fibrosis cytokine effective therapy in vivo inhibitor/antagonist insight metabolomics mortality mouse model new therapeutic target novel physical property pressure prevent progenitor response sudden cardiac death therapeutic target translational study

项目摘要

DESCRIPTION (provided by applicant): Cardiovascular disease is the leading cause of morbidity and mortality in the United States. Sustained cardiac hypertrophy represents one of the most common causes leading to heart failure. Once heart failure develops, the condition is irreversible and is associated with a very high mortality rate. Moreover, cardiac hypertrophy and failure are associated with an increase in both atrial and ventricular arrhythmias and sudden cardiac death. During our last funding cycle, we have demonstrated the beneficial effects of a novel class of soluble epoxide hydrolase (sEH) inhibitors in clinically relevant models of cardiac hypertrophy and failure. Treatment with sEH inhibitors (sEHIs) results in the prevention of ventricular myocyte hypertrophy and electrical remodeling in pressure overload and MI models. Our preliminary findings further demonstrate that treatment with sEHIs prevents cardiac fibroblast proliferation and fibrosis. These results are exciting because they demonstrate for the first time a broader salutary effects in cardiac remodeling (not limited to just myocyte hypertrophy) of this novel class of compounds. Thus, the central objective of this competing renewal is to test the beneficial effects of sEHIs in cardiac remodeling by modifying cardiac fibrosis. Additionally, since atrial fibrosis plays a central role in atrial fibrillation (AF), we urther propose that sEH may represent a new therapeutic target for the treatment of AF. Indeed, AF represents one the most common arrhythmias clinically and is associated with a significant increase in morbidity and mortality. Hence, new treatment paradigms for AF are likely to be highly impactful.

描述（由申请人提供）：心血管疾病是美国发病率和死亡率的主要原因。持续性心脏肥大是导致心力衰竭的最常见原因之一。一旦心力衰竭发展，病情就不可逆转，并且与非常高的死亡率有关。此外，心脏肥大和衰竭与心房和心室心律不齐和心脏猝死的增加有关。在我们的最后一个融资周期中，我们证明了一种新型的可溶性环氧化物水解酶（SEH）抑制剂在心脏肥大和失败的临床相关模型中的有益作用。用SEH抑制剂（SEHIS）治疗导致预防压力超负荷和MI模型中的心室肌细胞肥大和电重塑。我们的初步发现进一步表明，用SEHIS治疗可防止心脏成纤维细胞增殖和纤维化。这些结果令人兴奋，因为它们首次证明了这种新型化合物的心脏重塑（不限于肌细胞肥大）的更广泛的有益作用。因此，这种竞争性更新的核心目标是通过修饰心脏纤维化来测试SEHI在心脏重塑中的有益作用。此外，由于心房纤维化在房颤（AF）中起着核心作用，因此我们提出SEH可能代表了治疗AF的新治疗靶标。实际上，AF在临床上代表最常见的心律失常，并且与发病率和死亡率的显着增加有关。因此，AF的新治疗范例可能会产生很大的影响。