Computational Assessment of Galectin-3 Significance in Heart Failure Remodeling

Galectin-3 在心力衰竭重塑中的意义的计算评估

基本信息

批准号：
9487291
负责人：
Siamak Ardekani
金额：
$ 79.42万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9487291
关键词：
3-Dimensional Adverse effects Affect Anatomy Attenuated Behavior Cardiac Cardiac Myocytes Cells Cicatrix Cine Magnetic Resonance Imaging Clinical Collagen Collagen Fiber Computational algorithm Computing Methodologies Deposition Deterioration Development Diffusion Magnetic Resonance Imaging Drug Targeting Elements Ensure Environment Epidemic Equilibrium Etiology Evaluation Event Extracellular Matrix Fiber Fibroblasts Fibrosis Gadolinium Galectin 3 Geometry Heart Heart Injuries Heart failure Hypertension Immunohistochemistry Impairment Infarction Infiltration Inflammation Mediators Inflammatory Inflammatory Response Injury Intervention Knock-out Knockout Mice Left Left Ventricular Hypertrophy Left Ventricular Remodeling Left ventricular structure Macrophage Activation Magnetic Resonance Imaging Mathematics Mechanics Methods Microscopic Modeling Morbidity - disease rate Motion Movement Mus Muscle Muscle Cells Muscle Fibers Myocardial Myocardial Infarction Myocardial tissue Myocardium Myofibroblast Nature Necrosis Outcome Study Patients Pattern Perivascular Fibrosis Pharmacological Treatment Pharmacology Phase Phenotype Play Preparation Process Property Proteins Public Health Pump Relaxation Research Role Shapes Source Stress Structure Techniques Testing Three-dimensional analysis Time Tissues Torsion Translating Ventricular base constriction drug development heart function heart imaging human disease human model hypertensive heart disease improved in vivo interstitial macrophage macrophage product mechanical properties mortality mouse model novel novel therapeutic intervention novel therapeutics outcome forecast pressure prevent response therapeutic target tool treatment strategy

项目摘要

Project Summary Heart failure is a major growing public health problem with high morbidity and mortality. Despite extensive research and advances in drug development, there is still a strong demand for novel pharmacological agents that attenuate or reverse cardiac remodeling and prevent heart failure. Inflammatory mechanisms including macrophage activation and tissue fibrosis have been proposed to play an important role in cardiac remodeling and progression of heart failure. Interstitial fibrosis of viable myocardium following cardiac injury or pressure overload impairs tissue structure and behavior. Cells that are contributing to fibrosis of myocardium are primarily fibroblast and myofibroblats, which are phenotypically transformed fibroblast-like cells. Galectin-3 (a small protein) is emerging as a key player with a substantial role in the process of heart failure. It has been speculated that Galectin-3 promotes heart failure through involvement of multiple mechanisms including cardiac fibroblast proliferation, collagen deposition, and development of fibrosis. Excess collagen can potentially disturb extracellular matrix environment (ECM) resulting in alteration of spatial configuration of cardiac muscle fibers with respect to adjacent muscle elements. Alteration of muscle fiber configuration perturbs the cardiac clockwise and anticlockwise torsion, which is essential for normal pump function. Moreover, increase in myocardial collagen content could alter ventricular filling properties particularly by increasing diastolic stiffness. Clearly, an accurate assessment of left ventricular structure and function is an essential step to evaluate role of Galectin-3 inhibition in attenuating/reversing cardiac remodeling. In this study, sophisticated mathematical tools will be applied to in-vivo and ex-vivo cardiac images to identify correlation between Galectin-3 deletion and cardiac remodeling using two common murine models of heart failure (myocardial infarction and transverse aortic constriction). Immunohistochemistry techniques will be also used to evaluate Galectin-3 expression, presence of inflammatory cells (macrophages, fibroblasts and myofibroblasts), and tissue fibrosis in myocardial tissues. Outcome of this study provides novel mechanistic information that can guide the development of next generation therapeutic drugs targeting post-infarction and post-stress inflammatory response.

项目概要心力衰竭是一个日益严重的公共卫生问题，发病率和死亡率很高。尽管在药物开发方面进行了广泛的研究并取得了进展，但仍然存在强大的对减轻或逆转心脏重塑的新型药物的需求并预防心力衰竭。炎症机制，包括巨噬细胞激活组织纤维化被认为在心脏重塑中发挥重要作用和心力衰竭的进展。存活心肌间质纤维化心脏损伤或压力超负荷会损害组织结构和行为。细胞是引起心肌纤维化的主要是成纤维细胞和肌成纤维细胞，是表型转化的成纤维细胞样细胞。 Galectin-3（一种小蛋白质）是成为心力衰竭过程中发挥重要作用的关键参与者。它有据推测，Galectin-3 通过参与多种机制促进心力衰竭机制包括心脏成纤维细胞增殖、胶原蛋白沉积和纤维化的发展。过量的胶原蛋白可能会扰乱细胞外基质环境（ECM）导致心肌纤维空间结构的改变相对于相邻的肌肉元素。肌纤维构型的改变扰乱心脏顺时针和逆时针扭转，这对于正常运转至关重要泵功能。此外，心肌胶原含量的增加可能会改变心室充盈特性，特别是通过增加舒张硬度。显然，准确的左心室结构和功能的评估是评估作用的重要步骤 Galectin-3 抑制在减弱/逆转心脏重塑中的作用。在这项研究中，复杂的数学工具将应用于体内和离体心脏图像使用两种方法确定 Galectin-3 缺失与心脏重塑之间的相关性常见的小鼠心力衰竭模型（心肌梗塞和横主动脉收缩）。免疫组织化学技术也将用于评估 Galectin-3 表达、炎症细胞（巨噬细胞、成纤维细胞和肌成纤维细胞）和心肌组织中的组织纤维化。这项研究的结果提供了可以指导下一代发展的新颖机制信息针对梗塞后和应激后炎症反应的治疗药物。