Novel function and mechanism of CFTR in heart failure

CFTR在心力衰竭中的新功能和机制

基本信息

批准号：
8032346
负责人：
Dayue Darrel Duan
金额：
$ 21.07万
依托单位：
UNIVERSITY OF NEVADA RENO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-01-01 至 2012-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8032346
关键词：
ATP-Binding Cassette Transporters Address Age Animal Model Antioxidants Aorta Apoptosis Area Binding Bioenergetics Biological Biological Assay Cardiac Cardiac Myocytes Cause of Death Cell Survival Cessation of life Childhood Chloride Channels Clinical Clinical Research Clinical Treatment Complex Coupled Cystic Fibrosis Cystic Fibrosis Transmembrane Conductance Regulator Development Disease Drug Delivery Systems Echocardiography Etiology Fibrosis Functional disorder Goals Health Healthcare Systems Heart Heart Diseases Heart Hypertrophy Heart failure Homeostasis Human Hydrolysis Hypertrophy Immunologic Techniques Infection Injury Investigation Knockout Mice Knowledge Left Ventricular Remodeling Lesion Lipids Lung Masks Measurement Mediating Membrane Mitochondria Modeling Molecular Mutation Myocardial Myocardial dysfunction Outer Mitochondrial Membrane Oxidation-Reduction Oxidative Stress Patients Phosphorylation Physiological Play Preparation Property Protein Kinase Proteins Pulmonary Fibrosis Reactive Oxygen Species Regulation Regulator Genes Research Role Source Staging System Techniques Testing Tissues Translating Transportation United States Work Workload base cell injury clinical care clinically significant cysteinylglycine cystic fibrosis patients design functional restoration glutathione transporter heart cell long term hospitalization member mitochondrial membrane new therapeutic target novel pre-clinical pressure prevent response

项目摘要

DESCRIPTION (provided by applicant): The cystic fibrosis transmembrane conductance regulator (CFTR) is a unique member of the ATP-binding cassette (ABC) transporters superfamily, which functions as not only a transport but also a Cl- channel gated by protein kinase-dependent phosphorylation and cycles of ATP binding and hydrolysis. While the biophysical and pharmacological properties of the CFTR Cl- channels have been well characterized, the functional role of CFTR in the heart in the context of health and disease remains elusive. Recent clinical evidence points to a potential role of CFTR in heart failure (HF) but the exact functional and clinical significance of cardiac CFTR in myocardial hypertrophy and HF has not been studied. The long-term goal of our study is to determine the novel cardioprotective role of cardiac CFTR in cardiac hypertrophy and HF and to investigate the underlying molecular mechanisms. The short-term goal is to explore the functional and mechanistic bases of CFTR in the protection of cardiac myocytes against oxidative stress damage inflicted during myocardial hypertrophy and heart failure. To achieve these goals this proposal addresses the following specific aims: 1) to determine the functional role of CFTR in cardiac hypertrophy and failure through the demonstration of that targeted inactivation of CFTR gene causes a loss of compensatory response of cardiac function during the development of pathological myocardial hypertrophy and accelerate the progression of HF; 2) to determine whether CFTR is involved in redox regulation by demonstration of that a) CFTR is expressed on mitochondria, b) targeted inactivation of CFTR decreases mitochondrial concentration of 3- glutamyl-cysteinyl-glycine ([GSH]mito), and c) CFTR-mediated changes in [GSH]mito are closely coupled to regulation of mitochondrial function and cell viability under hypertrophy-induced oxidative stress. Experimental approaches will involve the use of CFTR knockout mouse, isolated working heart preparations, pressure-overload model of myocardial hypertrophy and HF, serial echocardiography, molecular biological and immunological techniques and mitochondrial GSH measurement and functional assays. The significance is that these studies will gain crucial evidence for the novel function of CFTR in protection of the heart against cardiac hypertrophy and failure and substantial knowledge on the novel mechanisms of redox regulation by CFTR-mediated mitochondrial GSH homeostasis, which will setup the stage for further understanding of the function and mechanism for the sarcolemmal and mitochondrial CFTR interactomes in the heart and pave a new path to the identification of novel therapeutic targets and thus translate these preclinical findings into clinical treatment of HF. PUBLIC HEALTH RELEVANCE: Heart diseases remain a major cause of human death in the United States. Clinical care for heart diseases is usually intensive and involves long term hospitalization, especially with heart failure, which creates a significant burden on the health care system. This proposal is to use state-of-the-art techniques to study how the heart can be protected from damages caused by increased work load. We focus on the novel function and molecular mechanism to protect the mitochondria of heart cells. As a result, it will provide new and crucial information for better understanding of the cause of heart disease and also new drug targets for the treatment of heart diseases.

描述（由申请人提供）：囊性纤维化跨膜电导调节剂（CFTR）是ATP结合盒（ABC）转运蛋白超级家族的独特成员，它不仅可以作为传输，而且还可以作为蛋白质激酶依赖的磷酸化磷酸化磷酸化和综合蛋白质的CL-通道。尽管CFTR CL-通道的生物物理和药理特性已经很好地表征了，但在健康和疾病的背景下，CFTR在心脏中的功能作用仍然难以捉摸。最近的临床证据表明，CFTR在心力衰竭（HF）中的潜在作用，但尚未研究心脏CFTR在心肌肥大和HF中的确切功能和临床意义。我们研究的长期目标是确定心脏CFTR在心脏肥大和HF中的新型心脏保护作用，并研究潜在的分子机制。短期目标是探索CFTR的功能和机械基础，以保护心肌细胞免受心肌肥大和心力衰竭造成的氧化应激损害。为了实现这些目标，该提案解决了以下特定目的：1）确定CFTR在心脏肥大中的功能作用和通过证明靶向CFTR基因的靶向失活的功能，从而导致心肌肥大的发展过程中心脏功能的补偿性丧失丧失，并使HF的进展加速HF； 2) to determine whether CFTR is involved in redox regulation by demonstration of that a) CFTR is expressed on mitochondria, b) targeted inactivation of CFTR decreases mitochondrial concentration of 3- glutamyl-cysteinyl-glycine ([GSH]mito), and c) CFTR-mediated changes in [GSH]mito are closely coupled to regulation of在肥大诱导的氧化应激下，线粒体功能和细胞活力。实验方法将涉及使用CFTR基因敲除小鼠，孤立的工作心脏制剂，心肌肥大和HF的压力超负荷模型，串行超声心动图，分子生物学和免疫学技术以及线粒体GSH的测量和功能分析。意义在于，这些研究将获得CFTR保护心脏肥大，失败的新功能的重要证据新型治疗靶标，从而将这些临床前发现转化为HF的临床治疗。公共卫生相关性：在美国，心脏病仍然是人类死亡的主要原因。心脏病的临床护理通常是密集的，涉及长期住院，尤其是心力衰竭，这会对医疗保健系统产生重大负担。该建议是使用最先进的技术来研究如何保护心脏免受工作负荷增加造成的损害。我们专注于保护心脏细胞线粒体的新功能和分子机制。结果，它将提供新的至关重要的信息，以更好地理解心脏病的原因以及治疗心脏病的新药物目标。