Computational Assessment of Galectin-3 Significance in Heart Failure Remodeling

项目摘要 心力衰竭是一个日益严重的公共卫生问题，发病率和死亡率都很高。 尽管在药物开发方面取得了广泛的研究和进展，但仍有很强的 对减弱或逆转心脏重塑的新型药物的需求 并预防心力衰竭。包括巨噬细胞激活在内的炎症机制 组织纤维化被认为在心脏重塑中起重要作用 和心力衰竭的进展。术后存活心肌的间质纤维化 心脏损伤或压力超负荷会损害组织结构和行为。单元格是 导致心肌纤维化的主要是成纤维细胞和肌成纤维细胞，它们 是表型转化的成纤维细胞样细胞。Galectin-3(一种小蛋白)是 在心力衰竭的过程中扮演着重要角色。它有 已经推测Galectin-3通过参与多个 机制包括心脏成纤维细胞增殖、胶原沉积和 纤维化的发展。过多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素。肌纤维形态的改变 扰乱心脏顺时针和逆时针扭转，这对正常来说是必不可少的 泵功能。此外，心肌胶原蛋白含量的增加可能会改变心室 充盈性能，特别是通过增加舒张期硬度。显然，一个准确的 评价左心室结构和功能是评价心脏功能的重要步骤 Galectin-3抑制在减弱/逆转心脏重构中的作用。在这项研究中， 复杂的数学工具将应用于体内和体外心脏图像，以 用两种方法确定Galectin-3缺失与心脏重构的相关性 常见的小鼠心力衰竭模型(心肌梗死和横主动脉 收缩)。免疫组织化学技术也将用于评估Galectin-3 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 可指导下一代发展的新型机械信息 针对脑梗塞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.