Cell-Matrix Contacts Regulate Age-Associated Cardiac Function

 描述(申请人提供)：心脏病是美国的主要死亡原因，随着寿命的持续延长，人类心血管恶化和心力衰竭的发生率急剧增加。随着年龄的延长，细胞微环境发生显着的重塑，导致心肌组织结构的病理改变，如纤维化和肥厚。这些改变很大程度上是由于细胞外基质(ECM)成分的沉积，对组织的机械性能产生不利影响，并导致收缩性能下降。为了确定什么遗传影响和细胞机制导致心功能随年龄下降，在遗传易处理的模型中研究年龄相关的心力衰竭是至关重要的。果蝇，俗称果蝇，由于人类基因的相对保守性，曾被用作心脏遗传学的模式生物，但由于其寿命短，也是研究年龄引起的心脏衰退的理想模型。心脏的多层设计提供了一个更简单的结构，用来研究任何与年龄相关的ECM重塑如何通过修改的ECM-胞浆-肌节机械转导改变层之间的机械耦合，从而对心肌细胞收缩产生不利影响。初步数据表明，通过舒张期内径缩小和心律失常增加，细胞外基质重塑和收缩之间存在相关性。以前用于测量果蝇被动心肌硬度的原子力显微镜(AFM)分析也发现了腹肌和底层心肌细胞间ECM层的硬度和厚度的差异。根据这些数据，我认为与年龄相关的ECM重构，即ECM组成和组装的变化，改变了苍蝇心脏各层之间的粘连串扰，导致了不同的基因型特异性心肌病。我将首先[1]研究果蝇品系腹侧肌层和心肌肌层之间细胞外基质的成分、结构和力学变化，以评估细胞外基质对年龄相关性舒张期下降的影响。然后，我将[2]从功能上评估主要的心脏细胞外基质蛋白在衰老过程中调节细胞-细胞外基质黏附的作用。利用果蝇心脏衰老模型，我希望能更好地了解体内细胞整合素-ECM串扰如何影响心脏组织内各层之间的力电耦合。

 DESCRIPTION (provided by applicant): Heart disease is the leading cause of death in the United States, and as lifespans continue to extend, the incidence of cardiovascular deterioration and heart failure in humans has dramatically increased. With prolonged aging there is significant remodeling within the cellular microenvironment leading to pathological alterations of myocardial tissue structure such as fibrosis and hypertrophy. These alterations largely result from deposition of extracellular matrix (ECM) components that adversely affect the mechanical properties of the tissue and lead to decreased contractile performance. Studying age-related heart failure in genetically tractable models is critical in order to determine what genetic influences and cellular mechanisms result in the decline of cardiac performance with age. Drosophila melanogaster, commonly known as the fruit fly, has been used previously as a model organism for cardiac genetics due to the relative conservation of human genes; however, it is also an ideal model for studying age-induced cardiac decline due to its short life span. The multilayered design of the heart provides a simpler structure in which to study how any age-associated ECM remodeling alters mechanical coupling between layers via modified ECM-costamere-sarcomere mechanotransduction to adversely impact cardiomyocyte contraction. Preliminary data suggests a correlation between ECM remodeling and contraction through reduced diastolic diameter and increased arrhythmicity. Atomic force microscopy (AFM) analysis previously used for measuring passive myocardial stiffness in Drosophila has also identified differences in the stiffness and thickness of the ECM layer between the ventral muscle and underlying cardiomyocytes. From these data, I propose that age-related ECM remodeling, i.e. ECM composition and assembly changes, alters the adhesive cross talk between fly heart layers, leading to distinct genotype-specific cardiomyopathies. I will first [1] examine ECM compositional, structural, and mechanical changes between the ventral and cardiomyocyte muscle layers in Drosophila strains to assess the effect of ECM on age-associated diastolic decline. I then will [2] functionally assess the contribution of major cardiac ECM proteins in mediating cell-ECM adhesion between layers during aging. Using the Drosophila cardiac aging model I hope to gain a better understanding of how in vivo cell integrin-ECM cross-talk affects mechanoelectric coupling of layers within cardiac tissue.