Desmoplakinopathies: Integrated Pathophysiology and Therapeutics

桥粒斑蛋白病：综合病理生理学和治疗学

基本信息

批准号：
10659458
负责人：
FADI GABRIEL AKAR
金额：
$ 67.36万
依托单位：
YALE UNIVERSITY
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：
2023-04-15 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10659458
关键词：
Address Adrenergic Agents Age Years Arrhythmia Bioreactors Calpain Cardiac Cardiomyopathies Cell Line Chronic Clinical Complex Desmosomes Development Disease Disease Progression Echocardiography Electrocardiogram Event Exercise Exhibits Failure Familial disease Female Fibrosis Frequencies Functional disorder Generations Genes Genetic Genetic Predisposition to Disease Heart Rate Heart failure Heritability Heterozygote Human Engineering In Vitro Incidence Individual Infiltration Inflammation Inherited Intercalated disc Intervention Intraperitoneal Injections Ion Channel Knock-in Left Link Maintenance Maps Measures Mechanics Mediating Molecular Mus Muscle Cells Mutation Myocardial dysfunction Operative Surgical Procedures Optics Pathogenicity Patients Pattern Penetrance Phase Prevention strategy Production Proteins Proteolysis Reactive Inhibition Reactive Oxygen Species Risk Secondary to Shunt Device Signal Transduction Stress Stretching Symptoms Syndrome Telemetry Testing Therapeutic Therapeutic Effect Time Toxic effect Variant Ventricular Ventricular Arrhythmia Work X-Ray Computed Tomography arrhythmogenic cardiomyopathy autosome calpain inhibitor calpastatin cardiac tissue engineering desmoplakin disease-causing mutation early onset endurance exercise experience experimental study gene environment interaction in vivo indexing innovation male mechanotransduction microCT mitochondrial dysfunction model design mouse model next generation novel overexpression pharmacologic small molecule stressor sudden cardiac death transmission process

项目摘要

PROJECT SUMMARY Arrhythmogenic Cardiomyopathy (ACM) is a heritable disease that bridges the gap between the cardiomyopathies and the inherited arrhythmia syndromes. In its early “concealed” phase, ACM promotes the incidence of ventricular arrhythmias in the absence of overt structural or mechanical remodeling. As the disease progresses, myocyte loss, inflammation, and fibrofatty infiltration emerge, culminating in biventricular failure and further risk of sudden cardiac death (SCD). The pathophysiological significance of the disease is underscored by the fact that ACM is a leading cause of SCD in young individuals < 35 years of age. Mutations in desmosomal proteins account for the majority (approx. 60%) of ACM cases, and in this project we focus on a form of ACM known as Desmoplakin (DSP) cardiomyopathy (DSP-CM). DSP-CM has recently emerged as a unique clinical entity that engenders a severe left-dominant form of the disease. DSP-CM is now well recognized to be a heritable disease that is transmitted in an autosomal dominant pattern, albeit with incomplete and highly variable penetrance. Indeed, a major challenge in the field has been the lack of ability to distinguish whom amongst carriers of pathogenic DSP variants are truly at risk of SCD and whom will go on to live healthy and symptom- free lives. This issue takes on added urgency given that the prevention strategy for SCD in DSP-CM is exercise restriction, a rather draconian measure for young healthy individuals, often athletes. The highly variable penetrance associated with DSP-CM as well as the typical mode of SCD that these patients exhibit highlight the importance of gene-environment interactions in unmasking disease pathogenicity. Our own recent work has identified calpain-mediated desmoplakin degradation as a key factor linking DSP mutations with the development of ACM and its exacerbation by exercise. Our central hypothesis is that: 1) calpain-mediated loss of myocyte DSP protein is a key molecular event that is unmasked by exercise and β-adrenergic stimulation, and 2) the pathogenic effects of DSP degradation at the intercalated disc (ID) are exacerbated by abnormal stretch-related mechanotransduction leading to arrhythmias and heart failure. We will address this dual hypothesis using a multi- scale approach encompassing complementary studies in human engineered heart tissues (hEHT) and innovative genetic and surgical mouse models that are designed to address the complex interactions between external stressors (increased preload) and genetic predisposition (DSP mutations) in the manifestation of DSP- CM. Our studies will enable us to tease out contributions of separate aspects of endurance exercise to myocyte dysfunction and expose pathophysiological mechanisms by which calpain vulnerability is unmasked by external stressors to promote early onset arrhythmias and heart failure progression. Finally, we will test novel gene and small molecule-based approaches to inhibit exercise-related calpain vulnerability while avoiding toxicity.

项目概要致心律失常性心肌病 (ACM) 是一种遗传性疾病，它弥补了心律失常性心肌病与心律失常性心肌病之间的差距。心肌病和遗传性心律失常综合征在其早期“隐藏”阶段，ACM 会促进在没有明显的结构或机械重塑的情况下室性心律失常的发生率。随着病情进展，出现肌细胞丢失、炎症和纤维脂肪浸润，最终导致双心室衰竭和心脏性猝死（SCD）的进一步风险强调了该疾病的病理生理学意义。事实上，ACM 是 35 岁以下年轻人发生 SCD 的主要原因。蛋白质占 ACM 病例的大多数（约 60%），在本项目中，我们重点关注 ACM 的一种形式称为桥粒斑蛋白（DSP）心肌病（DSP-CM）最近作为一种独特的临床出现。现在人们普遍认为，导致严重左为主型疾病的实体是一种疾病。以常染色体显性模式传播的遗传性疾病，尽管具有不完全性和高度可变性事实上，该领域的一个主要挑战是缺乏区分谁的能力。致病性 DSP 变异的携带者确实面临 SCD 的风险，但他们将继续健康生活，并且不会出现症状。鉴于 DSP-CM 中的 SCD 预防策略正在实施，这个问题变得更加紧迫。限制，对于年轻健康的人（通常是运动员）来说是一项相当严厉的措施。与 DSP-CM 相关的外显率以及这些患者表现出的典型 SCD 模式强调了我们最近的工作揭示了基因与环境相互作用在揭示疾病致病性方面的重要性。确定钙蛋白酶介导的桥粒斑蛋白降解是 DSP 突变与发育相关的关键因素 ACM 的发生及其因运动而加剧。我们的中心假设是：1) 钙蛋白酶介导的肌细胞损失。 DSP 蛋白是一个关键的分子事件，可以通过运动和 β-肾上腺素能刺激来揭示，并且 2) 异常拉伸相关加剧了闰盘 (ID) DSP 降解的致病作用我们将使用多种机制来解决这一双重假设。规模方法包括对人类工程心脏组织（hEHT）和创新的遗传和手术小鼠模型，旨在解决之间的复杂相互作用 DSP-表现中的外部应激源（增加的前负荷）和遗传倾向（DSP突变） CM：我们的研究将使我们能够梳理出耐力运动的各个方面对肌细胞的贡献。功能障碍并暴露病理生理机制，通过外部因素揭示钙蛋白酶的脆弱性最后，我们将测试新的基因和促进早期心律失常和心力衰竭进展的压力源。基于小分子的方法可抑制运动相关的钙蛋白酶脆弱性，同时避免毒性。