Computational Assessment of Galectin-3 Significance in Heart Failure Remodeling

项目摘要 心力衰竭是一个主要的日益严重的公共卫生问题，具有高发病率和死亡率。 尽管在药物开发方面进行了广泛的研究和进步， 对减弱或逆转心脏重塑的新型药理学试剂的需求 防止心力衰竭炎症机制，包括巨噬细胞活化 组织纤维化在心脏重塑中起重要作用 和心力衰竭的进展存活心肌间质纤维化 心脏损伤或压力过载损害组织结构和行为。的细胞 导致心肌纤维化的主要是成纤维细胞和肌纤维母细胞， 是表型转化的成纤维细胞样细胞。半乳糖凝集素-3（一种小蛋白）是 成为心力衰竭过程中的重要参与者。它有 据推测，半乳糖凝集素-3通过参与多种 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干扰细胞外基质 环境（ECM）导致心肌纤维空间构型的改变 相对于相邻的肌肉元件。肌纤维形态改变 干扰心脏顺时针和逆时针扭转，这是必不可少的正常 泵功能此外，心肌胶原含量的增加可改变心室肌的收缩功能， 填充性能，特别是通过增加舒张刚度。显然，一个准确的 左心室结构和功能的评估是评估作用的重要步骤， 半乳糖凝集素-3抑制在减弱/逆转心脏重塑中的作用。在本研究中， 复杂的数学工具将应用于体内和体外心脏图像， 用两种方法鉴定半乳糖凝集素-3缺失与心脏重塑相关性 常见的心力衰竭小鼠模型（心肌梗死和横主动脉 收缩）。还将使用免疫组织化学技术评价半乳糖凝集素-3 表达、炎性细胞（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 可以指导下一代开发的新的机械信息 靶向梗死后和应激后炎症反应的治疗药物。

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.