Functional Phenotyping of Cardiomyopathy by MRI

通过 MRI 分析心肌病的功能表型

基本信息

批准号：
7324812
负责人：
Xin Yu
金额：
$ 36.27万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-12-05 至 2010-04-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7324812
关键词：
Adult Animal Model Animals Apoptosis Architecture Arts Basement membrane Biomechanics Cardiac Cardiomyopathies Cardiovascular Diseases Cause of Death Child Complex Computer Simulation Congestive Heart Failure Cytoskeleton Data Defect Diffusion Dilatation - action Dilated Cardiomyopathy Disease Disease Progression Dissociation Dystrophin Extracellular Matrix Failure Fiber Functional disorder Gene Targeting Gene Transfer Techniques Glycoproteins Hamsters Health Care Costs Heart Heart Transplantation Histologic In Vitro Investigation Knock-out Laminin Lead Lesion Link Magnetic Resonance Imaging Measurement Mechanics Mesocricetus auratus Methods Microscopic Modeling Molecular Molecular Biology Motion Mus Mutation Myocardial Myocardial dysfunction Myocardium Pathological Dilatation Pattern Phenotype Process Property Proteins Research Rodent Model Role Staging Stress Structural Protein Structure Structure-Activity Relationship Techniques Technology Torsion United States Utrophin Ventricular Ventricular Function Ventricular Remodeling delta Sarcoglycan disability disease phenotype genetic analysis in vivo insight mdx mouse mouse model programs research study response technology development transmission process

项目摘要

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.

描述（由申请人提供）：该提案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（弥散张量 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中细胞外基质重塑而导致的心肌纤维结构的变化，并阐明心肌纤维结构的变化。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来阐明宏观结构变化和功能改变背后的分子/细胞变化。扩张型心肌病 (DCM) 的四种啮齿动物模型：T0-2 DCM 仓鼠（δ-肌聚糖缺陷）、mdx 小鼠（肌营养不良蛋白缺陷）、mdx/utm 小鼠（肌营养不良蛋白/肌营养不良蛋白双敲除）和 dy/ dy 小鼠（层粘连蛋白 alpha2 缺陷）将在 4.7T 研究扫描仪上进行表征。将采用计算模型将功能异常与微观水平上发生的心脏结构变化直接关联起来，以阐明导致 DCM 心肌功能障碍的机制。我们的具体目标是： 1. 使用 MRI 和免疫组织学方法表征心肌病叙利亚仓鼠 (T0-2) 在疾病不同阶段的功能和结构变化； 2.记录mdx、mdx/utrn和dy/dy小鼠心肌结构和局部心室壁运动的纵向变化； 3. 使用实验数据和计算模型来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。这是一个多学科项目，涉及技术开发和采用综合方法对常见心血管疾病进行研究。将应用实验和计算方法来了解导致其体内功能表现的病理生理过程的细胞机制。该提案中开发的方法将为阐明 DCM 以及其他心血管疾病的心功能障碍的分子机制提供新的手段。