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首页> 外文学位 >The Effects of Arrhythmogenic Right Ventricular Cardiomyopathy-Causing Proteins on the Mechanical and Signaling Properties of Cardiac Myocytes.
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The Effects of Arrhythmogenic Right Ventricular Cardiomyopathy-Causing Proteins on the Mechanical and Signaling Properties of Cardiac Myocytes.

机译：致心律失常的右室心肌病蛋白对心肌细胞机械和信号特性的影响。

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摘要

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by a high incidence of lethal ventricular arrhythmias, fibrofatty replacement of myocardium, and can account for up to 20% of sudden cardiac death (SCD) cases in the young. Typically involving autosomal dominant transmission, germline mutations in genes encoding desmosomal proteins have been identified as a cause of ARVC, although the pathogenesis of the disease is still unclear. While early detection and treatment can provide a normal life expectancy for the majority of patients, with less than 10% progressing to overt right ventricular failure, low genetic penetrance and epigenetic modifiers (such as endurance exercise) can make the condition difficult to diagnose. Addressing this clinical challenge requires a better understanding of the defective molecular mechanisms that underlie the disease. To that end, the goal of this dissertation is to provide insight into the effects of ARVC-causing mutant proteins on the mechanical and signaling properties of cardiac myocytes.;Using elastography and histological techniques, we begin by characterizing the structural and mechanical properties of the native right ventricular myocardium, particularly the right ventricular apex (RVA). Because the RVA is a key site for development of arrhythmias and a potential pacing target, a careful characterization of its structure and mechanical properties are essential for understanding its role in cardiac physiology. In the first section of this dissertation, we perform a systematic analysis of the structural features and mechanical strains in the heart, focusing on the RVA region.;More than half of ARVC patients exhibit one or more mutations in genes encoding desmosomal proteins. This has led many investigators to suggest that ARVC is a "disease of the desmosome" in which defective cell-cell adhesion plays a critical pathogenic role, although direct evidence for this hypothesis is lacking. To gain greater insights into potential mechanisms by which desmosomal mutations cause ARVC, we next characterize biomechanical properties and responses to shear stress (motivated by our results in the previous section) in neonatal rat ventricular myocytes expressing two distinct mutant forms of the desmosomal protein plakoglobin which have been linked to ARVC in patients. We show that ARVC-causing mutations in plakoglobin lead to altered cellular distribution of plakoglobin, without alterations in cell mechanical properties or certain early signaling pathways.;The identification of defective molecular mechanisms that are common across ARVC-patients remains a strategic area of research. Specifically, recent studies have investigated the mechanistic basis for different ARVC-causing mutations in hopes of identifying common defects in a signaling pathway -- information that could be used to develop diagnostic tests or identify therapeutic targets. In the last section of this dissertation, we investigate the effects of mutant plakophilin-2 expression, and repeat key experiments performed in the previous section to identify common defects in mechanical and signaling properties. We identify a common, underlying defect in ARVC pathogenesis. Specifically, we show that disease-causing mutations across different desmosomal proteins can cause the cell to respond abnormally to mechanical shear stress with respect to plakoglobin trafficking.
机译：致心律失常性右室心肌病（ARVC）的特点是致死性室性心律不齐的发生率高，心肌纤维脂肪替代，可占年轻猝死（SCD）病例的20％。尽管该病的发病机制尚不清楚，但通常已证实常染色体显性遗传途径中，编码桥粒蛋白的基因中的种系突变是ARVC的病因。尽管早期检测和治疗可以为大多数患者提供正常的预期寿命，但进展为明显的右心室衰竭的患者不到10％，但是低的基因渗透率和表观遗传修饰因子（例如耐力运动）会使该病难以诊断。解决这一临床挑战需要更好地了解造成该疾病的有缺陷的分子机制。为此，本论文的目的是深入了解引起ARVC的突变蛋白对心肌细胞的机械和信号特性的影响。利用弹性成像和组织学技术，我们首先表征其结构和机械特性。天然右心室心肌，尤其是右心室顶点（RVA）。由于RVA是心律不齐发展的关键部位和潜在的起搏目标，因此对其结构和机械性质进行仔细表征对于了解其在心脏生理中的作用至关重要。在本文的第一部分，我们对心脏的结构特征和机械应变进行了系统的分析，重点是RVA区域。一半以上的ARVC患者在编码桥粒蛋白的基因中出现一个或多个突变。这导致许多研究者认为ARVC是“桥粒的疾病”，其中缺乏缺陷的细胞间粘附起着关键的致病作用，尽管缺乏这一假设的直接证据。为了更深入地了解桥粒突变引起ARVC的潜在机制，我们接下来对新生大鼠心室肌细胞表达桥粒蛋白plakoglobin两种不同突变形式的生物力学特性和对切应力的响应（由上一节中的结果所激发）进行表征。已经与患者的ARVC相关。我们表明，引起斑白蛋白的ARVC突变导致改变了斑白蛋白的细胞分布，而没有改变细胞力学性质或某些早期信号传导途径。;在ARVC患者中常见的缺陷分子机制的鉴定仍然是研究的战略领域。具体而言，最近的研究已经调查了导致ARVC变异的各种机制，以期找出信号传导途径中的常见缺陷-这些信息可用于开发诊断测试或确定治疗靶标。在本文的最后一部分中，我们研究了突变的plakophilin-2表达的影响，并重复了在前一部分中进行的关键实验，以鉴定机械和信号特性中的常见缺陷。我们确定了ARVC发病机制中常见的潜在缺陷。具体而言，我们显示了跨不同桥粒蛋白的致病突变可导致细胞对与白血球蛋白运输有关的机械剪切应力作出异常反应。

著录项

  • 作者

    Hariharan, Venkatesh.;

  • 作者单位

    Columbia University.;

  • 授予单位 Columbia University.;
  • 学科 Biomedical engineering.;Biomechanics.
  • 学位 Ph.D.
  • 年度 2014
  • 页码 151 p.
  • 总页数 151
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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