Imaging of MMP activation and myocardial strains

MMP 激活和心肌应变的成像

• 批准号: 6951045
• 负责人: Albert J Sinusas
• 金额: $ 56.16万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-22 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6951045
• 关键词: autoradiography; bioimaging /biomedical imaging; biomechanics; cardiovascular imaging /visualization; enzyme activity; genetically modified animals; heart ventricle; laboratory mouse; metalloendopeptidases; microspectrophotometry; molecular /cellular imaging; molecular probes; myocardial infarction; swine; technology /technique development

DESCRIPTION (provided by applicant): Following myocardial infarction (MI) the left ventricle (LV) may undergo the process of remodeling, which represents the adverse changes in the structure, geometry and function of the LV. This post-MI remodeling is associated with important changes within the myocardial extracellular matrix (ECM) and is an independent predictor of increased morbidity and mortality following MI. Disruption of the ECM results in a loss of normal structural support, placing the myocardium under abnormal stress and strain, which in turn causes changes in myocardial geometry and function. The matrix metalloproteinases (MMPs) constitute a large family of proteolytic enzymes responsible for ECM degradation and remodeling. A clear cause/effect relationship between MMPs and the LV remodeling process has been demonstrated through the use of experimental studies. However, a non-invasive method for detecting and quantifying MMP activity in-vivo during the evolution of post-MI remodeling has yet to be developed and forms a critical component for translating these basic observations to clinical applicability. We have been developing high sensitivity MMP targeted molecular imaging approaches and cine magnetic resonance (MR) imaging methods in order to quantify regional MMP activity and changes in LV deformation and geometry post-MI. This combined molecular-mechanical approach will allow us to address the central hypothesis of this project; that enhanced MMP activation occurs following MI, is associated with altered regional myocardial deformation, contributes to an acceleration of adverse remodeling, and that the risk for MMP mediated post-MI remodeling can be identified and tracked through novel multimodality non-invasive imaging of MMP activation and LV deformation. This project will develop and validate a quantitative non-invasive approach for serial evaluation of MMP activation following myocardial infarction and relate regional changes in MMP activation to change in regional myocardial strain and microstructure. The targeted molecular imaging approach developed in this proposal should provide unique insights into the role of mechanical forces and MMP activation in the processes involved in ventricular remodeling, and translate to direct clinical applications that hold both prognostic and diagnostic potential.

描述（由申请人提供）： 跟随心肌梗塞（MI）左心室（LV）可能会经历重塑过程，这代表了LV的结构，几何形状和功能的不利变化。这种MI后重塑与心肌外基质（ECM）内的重要变化有关，并且是MI后发病率和死亡率增加的独立预测指标。 ECM的破坏会导致正常结构支撑的丧失，将心肌置于异常应力和应变下，这又导致心肌几何和功能的变化。基质金属蛋白酶（MMP）构成了负责ECM降解和重塑的大型蛋白水解酶。通过使用实验研究，已经证明了MMP与LV重塑过程之间的明显原因/作用关系。但是，一种用于检测和量化MMP活性在MI后重塑后体内的MMP活性的非侵入性方法尚未开发出来，并构成了将这些基本观察结果转化为临床适用性的关键组成部分。我们一直在开发高灵敏度MMP靶向分子成像方法和Cine磁共振（MR）成像方法，以量化区域MMP活性以及MI后LV变形和几何形状的变化。这种结合的分子力学方法将使我们能够解决该项目的中心假设。在MI之后发生这种增强的MMP激活，与区域心肌变形改变有关，有助于加速不良重塑，并且可以通过新型的多模态性非局限性非不利化的MMP激活和LV Adeformation识别MMP MI介导的MI后MI重塑的风险。该项目将开发并验证一种定量的非侵入性方法，用于在心肌梗塞后对MMP激活的序列评估，并将MMP激活的区域变化与区域心肌菌株和微观结构的变化相关联。本提案中开发的靶向分子成像方法应为机械力和MMP激活在涉及心室重塑的过程中的作用提供独特的见解，并转化为具有预后和诊断潜力的直接临床应用。