Functional Phenotyping of Cardiomyopathy by MRI

描述(由申请人提供)： 本研究的重点是确定抗肌营养不良蛋白-糖蛋白复合体(DGC)在细胞外基质重构中的作用及其对三维心肌纤维结构和室壁运动的影响。利用最先进的MR技术(扩散张量磁共振和心脏标记)，我们试图描述DGC和相关蛋白缺陷的心肌病心脏由于细胞外基质重塑而导致的心肌纤维结构的变化，并阐明这种结构变化对局部心肌收缩性能的影响。组织学和免疫细胞化学方法将被用来阐明宏观结构变化和功能变化背后的分子/细胞变化。四种扩张型心肌病(DCM)的啮齿动物模型，T0-2 DCM仓鼠(Delta-肌聚糖缺乏)，MDX小鼠(dystrophin缺乏)，mdx/utm小鼠(dystrophin/utroin双基因敲除)，和dy/dy小鼠(层粘连蛋白α2缺乏)，将在4.7T研究扫描仪上进行特征描述。在阐明扩张型心肌病心肌功能障碍的机制方面，计算模型将被用于在微观水平上将心脏结构的改变与功能异常直接联系起来。我们的具体目标是：1.用MRI和免疫组织学方法描述心肌病叙利亚仓鼠(T0-2)在疾病不同阶段的功能和结构变化；2.记录MDX、MDX/UTUN和dy/dy小鼠心肌结构和局部室壁运动的纵向变化；3.使用实验数据和计算模型预测心肌壁应力，并确定正常和疾病心脏的被动和主动材料特性。这是一个多学科的项目，既涉及技术开发，也涉及对一种常见心血管疾病的综合研究。实验和计算方法将被用来理解病理生理过程的细胞机制，这些过程负责它们在体内的功能表现。该方案中开发的方法将为阐明扩张型心肌病以及其他心血管疾病中心脏功能障碍的分子机制提供新的手段。

DESCRIPTION (provided by applicant): The focus of this proposal is to determine the role of dystrophin-glycoprotein complex (DGC) in extracellular matrix remodeling and its impact on the three-dimensional myocardial fiber structure and ventricular wall motion. Using state-of-the-art MR technology (diffusion tensor MRI and cardiac tagging), we seek to characterize changes in myocardial fiber structure due to remodeling of the extracellular matrix in cardiomyopathic hearts with defects in DGC and associated proteins, and to elucidate the impact of such structural changes on regional myocardial contractility. Histologic and immunocytochemical methods will be employed to elucidate molecular/cellular changes that underlie the macroscopic structural changes and functional alterations. Four rodent models of dilated cardiomyopathy (DCM), the T0-2 DCM hamster (delta-sarcoglycan-deficient), the mdx mouse (dystrophin-deficient), the mdx/utm mouse (dystrophin/utrophin double knockout), and the dy/dy mouse (laminin alpha2-deficient), will be characterized on a 4.7T research scanner. Computational modeling will be employed to directly correlate functional abnormalities to changes in cardiac structure that occur at microscopic levels in elucidating the mechanisms that are responsible for myocardial dysfunction in DCM. Our specific aims are: 1. To characterize functional and structural changes in cardiomyopathic Syrian hamster (T0-2) at distinct stages of the disease using both MRI and immunohistological methods; 2. To document longitudinal changes in myocardial structure and regional ventricular wall motion in mdx, mdx/utrn, and dy/dy mouse; 3. To use experimental data and computational models to predict myocardial wall stress and to determine passive and active material properties of normal and diseased hearts. This is a multi-disciplinary project that involves both technology development and investigation of a common cardiovascular disease with integrative approaches. Experimental and computational approaches will be applied to understand cellular mechanisms of pathophysiological processes that are responsible for their functional manifestations in vivo. Methods developed in this proposal will provide new means in elucidating the molecular mechanism of cardiac dysfunction not only in DCM but also in other cardiovascular diseases.