MOLECULAR POLARIZATION IN DYSSYNCHRONOUS HEARTS AND CRT

不同步心脏和 CRT 中的分子极化

• 批准号: 6951260
• 负责人: Jennifer E Van Eyk
• 金额: $ 25.93万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-15 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6951260
• 关键词: biological signal transduction; calcium flux; cardiac myocytes; cardiovascular disorder therapy; cellular pathology; disease /disorder model; dogs; electronic pacemaker; endocardium; enzyme activity; functional /structural genomics; gene expression; heart conduction system; heart contraction; heart disorder; heart electrical activity; heart failure; heart ventricle; mechanical stress; microarray technology; molecular pathology; pathologic process; posttranslational modifications; protein kinase; protein quantitation /detection; proteomics; ventricular hypertrophy

This subproject focuses on defining the influence and mechanisms whereby cardiac dyssynchrony with and without underlying cardiac failure induces local molecular and cellular transmural abnormalities. This project stems from our recent discovery that dyssynchrony in a failing heart results in striking localized changes in the expression of proteins involved with calcium handling, hypertrophic signaling, and electrical conduction. These changes are particularly concentrated in the endocardial layer of the late-activated territory, the region predicted to have the highest level of wall stress. Neighboring mid-epicardial tissue displays expression more akin to that observed in the opposing wall (both epi and endo layers). This highlights a localized transmural molecular polarization that can serve as an important substrate for why dyssynchrony is a major risk in heart failure patients. In addition to providing a more comprehensive analysis of the ventricular molecular and cellular effects from dyssynchrony in failure, this subproject will test the reversibility of these changes by means of cardiac resynchronization. There are three specific aims. The first aim will identify signaling cascades triggered in the dyssynchronous heart, clarify their specificity to endocardial layers in late (high stress)-activated myocardium, and determine the synergistic role of co-existing dilated cardiac failure. Two major strategies are used: specific testing of candidate proteins/genes involved with growth, remodeling, and myocyte calcium handing, and a broader analysis of myocyte sub-proteome (cytosolic, sarcomplasmic reticulum, gap junction) and transcriptome (canine array chip). The second aim will integrate these molecular findings with direct analysis of the cellular functional and calcium handling impact of dyssynchrony in cardiomyocytes derived from early versus late activated territories from both endocardial and mid-wall layers. The third aim tests the reversibility of molecular and cellular abnormalities induced by dyssynchrony by a subsequent period of cardiac bi-ventricular resynchronization. These studies will provide the first test of such reversibility, and integrate changes at molecular and cellular levels to at the whole organ level.

该副本的重点是定义具有和没有潜在心脏衰竭的心脏异常的影响和机制，可诱导局部分子和细胞透壁异常。该项目源于我们最近的发现，即心脏失败的异质性导致钙处理，肥厚信号和电导传导所涉及的蛋白质表达的局部变化。这些变化尤其集中在晚期活化区域的内膜层，该地区预计具有最高水平的壁应力。相邻的中心组织显示的表达更类似于在相反的壁（EPI和ENDO层）中观察到的表达。这突出了一种局部的透明分子极化，可以作为为什么失调症是心力衰竭患者的主要风险的重要底物。除了对失败中的室内分子和细胞效应提供更全面的分析外，该副标将通过心脏重新同步测试这些变化的可逆性。有三个特定的目标。第一个目的将确定在异步心脏中触发的信号传导级联反应，阐明它们对晚期（高应激）激活的心肌对心内膜层的特异性，并确定共存扩张的心脏衰竭的协同作用。使用了两种主要策略：候选蛋白/基因的特定测试 涉及生长，重塑和心肌钙的交接，以及对肌细胞亚蛋白质组（胞质，肉瘤性网状，间隙连接）和转录组（犬阵列芯片）的更广泛分析。第二个目的将将这些分子发现与对源自心内膜和中壁层的早期激活领土和晚期活化领土的心肌细胞的细胞功能和钙处理影响直接分析。第三个目的测试了随后的心脏双室重新同步时期，由异议障碍引起的分子和细胞异常的可逆性。这些研究将提供这种可逆性的首次测试，并将分子和细胞水平的变化与整个器官水平的变化相结合。