Advancing cBIN1 Therapy to Large Preclinical Animals

将 cBIN1 疗法推广至大型临床前动物

基本信息

批准号：
10456878
负责人：
TingTing Hong
金额：
$ 22.88万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10456878
关键词：
Acute Adrenergic Agents Affect Age Age-Years Aging American Animal Model Animals Biochemical Biological Markers Blood Budgets Ca(2+)-Transporting ATPase Calcium Canis familiaris Cardiac Cardiac Myocytes Cellular biology Chronic Clinical Trials Congestive Heart Failure Coupled Coupling Data Dependovirus Deterioration Development Diastole Diastolic heart failure Diffusion Echocardiography Edema Electrons Excision Exclusion Failure Functional disorder Goals Heart Heart Atrium Heart failure Hospitalization Human Ice Image Imaging Device Impairment Individual Injections Ions L-Type Calcium Channels Medicare Medicine Membrane Membrane Microdomains Methods Modeling Monitor Morbidity - disease rate Mus Muscle Muscle Cells Myocardial Myocardial dysfunction Myocardium Outcome Pathologic Patients Physiology Population Proteins Publishing Recovery Relaxation Research Resolution Rodent Rodent Model Ryanodine Receptors SERCA2a Sarcoplasmic Reticulum Surface Symptoms Syndrome Tachycardia Testing Therapeutic Time Translating Treatment Efficacy Treatment Failure United States United States National Institutes of Health Ventricular Work base biochemical tools canine model cellular targeting cost efficacy study extracellular functional restoration gene therapy heart function hemodynamics improved in vivo mortality novel pre-clinical pressure recruit reuptake therapeutic target

项目摘要

Heart failure (HF) is a major cardiac syndrome with high mortality and morbidity which increases with age. For individuals 65 years of age and older, heart failure related hospitalization is the single greatest cost to the Medicare budget. In normal ventricular cardiomyocytes, beat-to-beat contraction and relaxation require coordinated systolic calcium release at dyads at transverse tubules (t-tubules, TT) and sarcoplasmic reticulum (SR) and diastolic calcium removal mainly through SR reuptake via Ca2+-ATPase (SERCA2a). A typical pathophysiology of failing cardiomyocytes is weakened calcium transients due to abnormal systolic calcium release from dyads as well as impaired diastolic removal due to altered SERCA2a activity. Central to the weakened transient is disorganization of TTs, their microdomains, and the calcium handling machinery. We recently identified that the calcium regulating cardiac bridging inte- grator 1 (cBIN1) forms TT microdomains and that cBIN1 is decreased in both systolic and diastolic HF. In rodent models, exogenous cBIN1 recovers failing myocardium. The overall objective here is to identify whether the cBIN1-microdomain targeting gene therapy can be translated from rodent studies to preclin- ical studies in a large animal model of HF. Our central hypothesis is that cBIN1-microdomains are dis- rupted in a canine model of chronic atrial pacing-induced HF, which can be rescued by exogenous cBIN1 gene therapy, allowing for recovery of failing myocardium. Two aims are proposed to first explore abnormal remodeling of subcellular microdomains in fail- ing cardiomyocytes from canine hearts subjected to tachy-pacing induced HF. Using biochemical and imaging tools, we will also determine the critical cellular point at which HF will require gene therapy. The second aim is proposed to study the efficacy of adeno associated virus 9 (AAV9)-transduced exog- enous cBIN1 in rescuing myocardial dysfunction and HF progression. A well-established canine model of chronic rapid atrial pacing-induced HF will be used to evaluate cardiomyocyte remodeling, functional deterioration, HF progression, as well as the therapeutic efficacy of intramyocardial injection of AAV9 transducing cBIN1 or a control protein GFP. Building on preliminary data, we will evaluate HF develop- ment by monitoring echocardiography recordings, hemodynamics, systemic symptoms, and blood available biomarkers. Our contribution here is expected to identify whether and how diminished cBIN1-microdomains are critical for reduced cardiac function in failing canine hearts, and whether exogenous cBIN1 can res- cue these hearts. The contribution is significant because it introduces a first in class HF therapeutic that targets the cellular remodeling of failing myocardium. Based on published and preliminary data, we ex- pect both a positive inotropic effect and lusitropic effect from exogenous cBIN1 therapy.

心力衰竭（HF）是一种主要的心脏综合征，死亡率高和发病率增加随着年龄的增长。对于65岁及以上的个人，与心力衰竭有关的住院治疗是单一的医疗保险预算的最大成本。在正常的心室心肌细胞中，beat to-beat收缩和放松需要在横向小管（T-pubules，tt）和肌质网（SR）和舒张钙的去除主要是通过Ca2+-ATPase通过SR再摄取（SERCA2A）。衰竭心肌细胞的典型病理生理学是由于从二元组中释放出异常的收缩钙以及因改变而导致的舒张压去除受损 SERCA2A活动。瞬态弱点的核心是TTS的混乱，它们的微区和钙处理机械。我们最近确定，调节心脏桥接的钙 - GRATOR 1（CBIN1）形成TT微域，并且在收缩期和舒张期HF中CBIN1均降低。在啮齿动物模型中，外源CBIN1恢复了心肌失败。这里的总体目标是确定 CBIN1-微生结构域靶向基因疗法是否可以从啮齿动物研究转化为preclin- 大型动物模型的研究。我们的核心假设是CBIN1-微生物域是不明显的在慢性心房起搏诱导的HF的犬模型中破裂，可以通过外源CBIN1营救基因疗法，可以恢复心肌失败。提出了两个目的，以探索失败 - 细胞微区的异常重塑 - 从犬心受到激进的诱导HF的犬心脏的心肌细胞。使用生化和成像工具，我们还将确定HF需要基因治疗的关键细胞点。提出的第二个目的是研究Adeno相关病毒9（AAV9）转导的Exog-的功效 CBIN1在营救心肌功能障碍和HF进展方面。建立良好的犬类模型慢性心房起搏诱导的HF的HF将用于评估心肌细胞重塑，功能性恶化，HF进展以及AAV9心脏内注射的治疗功效转导CBIN1或对照蛋白GFP。在初步数据的基础上，我们将评估HF开发 - 通过监测超声心动图记录，血液动力学，全身症状和血液可用的生物标志物。我们在这里的贡献预计将确定CBIN1-Microdomain是否以及如何减少对于失败的犬心中的心脏功能降低至关重要，以及外源性CBIN1是否可以解决提示这些心。这项贡献很重要，因为它引入了HF类治疗中的第一个靶向失败心肌的细胞重塑。根据已发布和初步数据，我们将促进外源CBIN1治疗的阳性肌力作用和lusitropic效应。