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.

摘要 心力衰竭(HF)是一种死亡率和发病率都很高的主要心脏综合征。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特征是 钙通道和兰诺定收缩期钙释放异常所致的钙瞬变减弱 受体二联体和SERCA2a活性改变所致的舒张期收缩功能受损。钙的活性受损 处理蛋白与心力衰竭时T小管(TT)的病理性重构有关。具体地说，在高频期间， TT微区丢失，随之而来的是钙处理机制的中断。 我们最近发现，钙离子调控的心脏桥联蛋白可能存在一个治疗靶点。 Grator 1(CBIN1)，用于组织TT微域。外源性cBIN1治疗挽救了啮齿动物的心衰。已经过去了- 本提案的所有目的是确定cBIN1微域靶向基因治疗是否可以反式转移。 用于非缺血性心肌病的大型动物模型。我们的中心假设是cBIN1-microdo- 在小型猪慢性心脏起搏诱导的心衰模型中，动脉被破坏，这可以通过以下方法恢复 CBIN1基因治疗挽救心肌细胞显微解剖及心功能。 首次提出两个目的来探索亚细胞细胞器和微域的异常重塑 起搏导致心力衰竭的小型猪心脏衰竭的心肌细胞。使用生化和成像技术 工具，我们还将确定心肌重构的关键病理生理点，在这个点上，心衰进展- 锡安是不可逆转的。第二个目的是研究腺相关病毒9型(AAV9)的疗效。 转导外源性cBIN1在抢救心肌功能不全和心力衰竭进展中的作用。小型猪模型的非 缺血性心肌病将用于评价AAV9-cBIN1基因治疗的疗效。我们的 初步数据表明，单次小剂量静脉注射AAV9-cBIN1可以完全 正常射血分数并诱导小型猪心脏扩张后的逆行重构 失败了。在这些初步研究的基础上，我们将通过监测来评估cBIN1基因治疗在抢救心衰中的作用。 超声心动图记录，血流动力学，全身症状，血液可用标志物，以及亚 TT膜和钙离子处理机的细胞组织。 我们的贡献有望确定cBIN1微域是否以及如何对心脏 在衰竭的小猪心脏中起作用。这一贡献意义重大，因为它将引入一种新的HF疗法， 它通过保存TT膜上的cBIN1-微域来纠正钙信号的异常。 这项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， 将改善心脏变力、心脏震颤和患者死亡率。