Correcting Cardiac Microdomains Reverses Non-Ischemic Cardiomyopathy

纠正心脏微区可逆转非缺血性心肌病

• 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
• 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

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）是一种主要的心脏综合征，具有高死亡率和发病率。但是治疗选择 缺乏主要靶向心肌失败的目标。失败心肌细胞的典型病理生理学是 由于从钙通道释放异常的收缩钙和瑞亚氨氨酸而导致的钙瞬变弱 由于SERCA2A活性改变而导致的受体二元组和舒张期障碍。钙的活性受损 处理蛋白质与心力衰竭期间T管（TT）的病理重塑有关。具体而言，在HF期间 TT微区域丢失，因此钙处理机械的破坏。 我们最近确定，调节心脏桥接的钙可能存在治疗靶标 组织TT微域的GRATOR 1（CBIN1）。外源性CBIN1治疗在啮齿动物中拯救了HF。超过 该提案中的所有目的都是确定靶向基因疗法的CBIN1-微生结构域是否可以转移 - 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- 在慢性心室起搏诱导的HF的微型模型中，电源被破坏，可以通过 CBIN1基因治疗用于救援心肌细胞微型解剖以及心脏功能。 提出了两个目标，以探索亚细胞器和微域的异常重塑 Minipig心脏的心肌细胞失败，而起搏引起的HF失败。使用生化和成像 工具，我们还将确定心肌重塑的临界病理生理点，其中HF前进 - sion是不可逆转的。提出的第二个目的是研究Adeno相关病毒9（AAV9） - 在挽救心肌功能障碍和HF进展方面，转导外源性CBIN1。非 - 的漫画模型 缺血性心肌病将用于评估AAV9-CBIN1基因治疗的治疗益处。我们的 初步数据令人惊讶，单次低剂量的静脉注射AAV9-CBIN1可以完全 标准化射血分数并诱导心脏中脑室扩张的反向重塑 失败。在这些初步研究的基础上，我们将通过监视HF来评估CBIN1基因疗法 超声心动图记录，血液动力学，全身症状和血液可用标记以及亚 TT膜和钙处理机械的细胞组织。 期望我们在这里做出的贡献将确定CBIN1-Microdomain是否对心脏至关重要 在失败的小型心脏中发挥作用。这项贡献很重要，因为它将引入新的HF治疗性， 通过在TT膜上保留CBIN1-微分类域，可以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脏肌肉特定疗法 将改善心脏障碍，心脏lusitropy和患者死亡率。