Cell-Matrix Contacts Regulate Age-Associated Cardiac Function

 描述（由申请人提供）：心脏病是美国的主要死因，随着寿命的持续延长，人类心血管恶化和心力衰竭的发病率急剧增加。随着衰老的延长，细胞微环境内存在显著的重塑，导致心肌组织结构的病理学改变，例如纤维化和肥大。这些改变主要是由于细胞外基质（ECM）组分的沉积，其不利地影响组织的机械性质并导致收缩性能降低。在遗传学易处理的模型中研究年龄相关性心力衰竭对于确定哪些遗传影响和细胞机制导致心脏性能随年龄下降至关重要。黑腹果蝇（Drosophila melanogaster），通常被称为果蝇，由于人类基因的相对保守性，以前曾被用作心脏遗传学的模式生物;然而，由于其寿命短，它也是研究年龄诱导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，其中研究任何年龄相关的ECM重塑如何通过修饰的ECM-肋节-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，ECM重塑和收缩之间的相关性，通过减少舒张直径和增加收缩。以前用于测量果蝇被动心肌硬度的原子力显微镜（AFM）分析也确定了腹肌和底层心肌细胞之间ECM层的硬度和厚度的差异。从这些数据中，我提出，年龄相关的ECM重塑，即ECM的组成和组装的变化，改变了苍蝇心脏层之间的粘合剂串扰，导致不同的基因型特异性心肌病。我将首先[1]检查果蝇品系中腹侧和心肌细胞肌肉层之间的ECM组成，结构和机械变化，以评估ECM对年龄相关舒张功能下降的影响。然后，我将[2]功能性地评估主要心脏ECM蛋白在老化过程中介导细胞-ECM层之间粘附的贡献。使用果蝇心脏衰老模型，我希望能更好地了解如何在体内细胞整合素ECM串扰影响心肌组织内的层机电耦合。

 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.