Functional Phenotyping of Cardiomyopathy by MRI

描述（由申请人提供）： 本研究的重点是确定肌营养不良蛋白-糖蛋白复合物（DGC）在细胞外基质重塑中的作用及其对三维心肌纤维结构和心室壁运动的影响。使用最先进的MR技术（扩散张量MRI和心脏标记），我们试图描述由于DGC和相关蛋白缺陷的心肌病心脏细胞外基质重塑引起的心肌纤维结构变化，并阐明这种结构变化对局部心肌收缩力的影响。将采用组织学和免疫细胞化学方法阐明宏观结构变化和功能改变的分子/细胞变化。将在4.7 T研究扫描仪上表征四种扩张型心肌病（DCM）啮齿动物模型，即T0-2 DCM仓鼠（δ-肌聚糖缺陷型）、mdx小鼠（肌营养不良蛋白缺陷型）、mdx/utm小鼠（肌营养不良蛋白/肌营养不良蛋白双敲除型）和dy/dy小鼠（层粘连蛋白α 2缺陷型）。将采用计算建模将功能异常与微观水平上发生的心脏结构变化直接相关，以阐明DCM中心肌功能障碍的机制。我们的具体目标是：1.采用MRI和免疫组化方法，研究心肌病叙利亚仓鼠（T0-2）在不同阶段的功能和结构变化。观察mdx、mdx/utrn和dy/dy小鼠心肌结构和局部室壁运动的纵向变化。使用实验数据和计算模型预测心肌壁应力，并确定正常和患病心脏的被动和主动材料特性。这是一个多学科的项目，涉及技术开发和研究一种常见的心血管疾病的综合方法。实验和计算的方法将被应用于了解细胞机制的病理生理过程，负责其功能表现在体内。该方法的建立为阐明扩张型心肌病及其他心血管疾病心功能不全的分子机制提供了新的手段。

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.