Correcting Cardiac Microdomains Reverses Non-Ischemic Cardiomyopathy

纠正心脏微区可逆转非缺血性心肌病

基本信息

批准号：
10720077
负责人：
TingTing Hong
金额：
$ 61.6万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-05 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10720077
关键词：
Affect Animal Model Animals Architecture Biochemical Biological Biological Markers Blood Calcium Calcium Signaling Cardiac Cardiac Myocytes Cardiomyopathies Cells Chronic Clinical Trials Congestive Heart Failure Data Dependovirus Deterioration Development Dilated Cardiomyopathy Dose EFRAC Echocardiography Electron Microscopy Epidemic Evaluation Excision Failure Functional disorder Goals Government Heart Heart failure Human Image Imaging Device Impairment Injections L-Type Calcium Channels Left Ventricular Ejection Fraction Left Ventricular Function Link Medical Membrane Membrane Microdomains Methods Microanatomy Miniature Swine Modeling Monitor Morbidity - disease rate Mus Muscle Muscle Cells Myocardial Myocardial dysfunction Myocardium Organelles Outcome Pathologic Pathway interactions Patients Persons Physiology Proteins Recovery Relaxation Research Rodent Rodent Model Role Ryanodine Receptor Calcium Release Channel SERCA2a Science Stress Symptoms Syndrome Tachycardia Testing Text Therapeutic Translating Treatment Efficacy United States United States National Institutes of Health Ventricular Ventricular Remodeling Work biochemical tools efficacy study gene therapy heart function heart preservation hemodynamics improved in vivo innovation intravenous injection microscopic imaging mortality novel pre-clinical reconstitution reduce symptoms restoration therapeutic target translational potential

项目摘要

Summary Heart failure (HF) is a major cardiac syndrome with high mortality and morbidity. Yet therapeutic options that primarily target failing heart muscle are lacking. The typical pathophysiology of failing cardiomyocytes is weakened calcium transients due to abnormal systolic calcium release from calcium channel and ryanodine receptor dyads and impaired diastolic removal due to altered SERCA2a activity. Impaired activity of the calcium handling proteins is linked to pathologic remodeling of t-tubules (TT) during heart failure. Specifically, during HF, TT microdomains are lost, with consequent disruption of the calcium handling machinery. We recently identified that a therapeutic target may exist in the calcium regulating cardiac bridging inte- grator 1 (cBIN1) which organizes TT microdomains. Exogenous cBIN1 therapy rescues HF in rodents. The over- all objective in this proposal is to identify whether the cBIN1-microdomain targeting gene therapy can be trans- lated to a large animal model of non-ischemic cardiomyopathy. Our central hypothesis is that cBIN1-microdo- mains are disrupted in a minipig model of chronic ventricular pacing-induced HF, which can be recovered by cBIN1 gene therapy for rescue cardiomyocyte microanatomy as well as cardiac function. Two aims are proposed to first explore abnormal remodeling of subcellular organelle and microdomains in failing cardiomyocytes from minipig hearts failing from pacing-induced HF. Using biochemical and imaging tools, we will also determine the critical pathophysiological point of myocardial remodeling at which HF progres- sion is irreversible. The second aim is proposed to study the efficacy of adeno associated virus 9 (AAV9)- transduced exogenous cBIN1 in rescuing myocardial dysfunction and HF progression. The minipig model of non- ischemic cardiomyopathy will be used to evaluate the therapeutic benefit of AAV9-cBIN1 gene therapy. Our preliminary data are striking that a single low dose of intravenous injection of AAV9-cBIN1 can fully normalize ejection fraction and induce reverse remodelling of dilated ventricles in minipigs with heart failure. Building on these preliminary studies, we will evaluate cBIN1 gene therapy in rescuing HF by monitoring echocardiography recordings, hemodynamics, systemic symptoms, and blood available markers, as well as sub- cellular organization of the TT membrane and the calcium handling machinery. Our contribution here is expected to identify whether and how cBIN1-microdomains are critical for cardiac function in failing minipig hearts. This contribution is significant because it will introduce a new HF therapeutic, which corrects calcium signaling abnormalities through preservation of cBIN1-microdomains at TT membrane. The proposed research is innovative because it introduces a new class of cardiac muscle specific therapy that will improve cardiac inotropy, cardiac lusitropy, and patient mortality.

概括心力衰竭（HF）是一种具有高死亡率和发病率的主要心脏综合征。然而治疗选择缺乏主要针对衰竭心肌的药物。衰竭心肌细胞的典型病理生理学是由于钙通道和兰尼定异常收缩期钙释放，钙瞬变减弱 SERCA2a 活性改变导致受体二元体和舒张期清除受损。钙的活性受损处理蛋白与心力衰竭期间 T 管 (TT) 的病理重塑有关。具体来说，在高频期间， TT 微区丢失，钙处理机制随之中断。我们最近发现，钙调节心脏桥接蛋白中可能存在一个治疗靶点。 grator 1 (cBIN1) 组织 TT 微域。外源性 cBIN1 疗法可挽救啮齿类动物的心力衰竭。过度该提案的所有目标是确定 cBIN1 微结构域靶向基因疗法是否可以跨与非缺血性心肌病的大型动物模型有关。我们的中心假设是 cBIN1-microdo- 在慢性心室起搏引起的心力衰竭的小型猪模型中，电源被破坏，可以通过以下方法恢复： cBIN1 基因治疗可挽救心肌细胞显微解剖结构和心脏功能。提出两个目标，首先探索亚细胞器和微区的异常重塑小型猪心脏因起搏引起的心力衰竭而导致的心肌细胞衰竭。使用生化和成像工具，我们还将确定心力衰竭进展的心肌重塑的关键病理生理学点锡安是不可逆转的。第二个目标是研究腺相关病毒9号（AAV9）的功效—— 转导外源性 cBIN1 可挽救心肌功能障碍和心力衰竭进展。非小型猪模型缺血性心肌病将用于评估 AAV9-cBIN1 基因治疗的治疗效果。我们的初步数据令人震惊，单次低剂量静脉注射 AAV9-cBIN1 可以完全使射血分数正常化并诱导小型猪扩张心室的逆重塑失败。在这些初步研究的基础上，我们将通过监测来评估 cBIN1 基因疗法在挽救心力衰竭方面的作用超声心动图记录、血流动力学、全身症状和血液可用标记物以及亚 TT 膜的细胞组织和钙处理机制。我们在这里的贡献预计将确定 cBIN1 微域是否以及如何对心脏至关重要在小型猪心脏衰竭中发挥作用。这一贡献意义重大，因为它将引入一种新的 HF 治疗方法，它通过在 TT 膜上保留 cBIN1 微结构域来纠正钙信号传导异常。拟议的研究具有创新性，因为它引入了一种新的心肌特异性疗法，将改善心脏正性肌力、心脏松弛性和患者死亡率。