Dynamic Role of Hyaluronan in Ventricular Remodeling

项目摘要 细胞外基质（ECM）为心肌提供结构和功能支持;然而，心脏 故障改变ECM的组成。ECM由许多蛋白质、脂质和脂质组成， 但它们的功能在很大程度上是未知的。我们发现ECM中最丰富的成分之一， 透明质酸（HA）在心肌梗死后蓄积;然而，HA在梗死后的作用- 引起的心力衰竭尚不清楚。成纤维细胞是参与心室重塑的主要细胞类型。一旦 活化后，成纤维细胞增殖并产生ECM组分，如胶原和HA。这些事件 与急性瘢痕形成和慢性心室重塑有关。在这个项目中，我将探索 成纤维细胞衍生的HA影响细胞外基质。具体来说，我将研究成纤维细胞胶原蛋白 当操纵HA代谢时分泌。此外，我将研究成纤维细胞衍生的 HA有助于MI后的急性瘢痕形成。最后，我将确定成纤维细胞衍生的 透明质酸有助于慢性心室重塑。我们认为，HA积累的急剧增加 是急性心肌梗死后瘢痕形成所必需的;然而，HA的持续过量产生引起了 在最初的疤痕之外形成纤维化因此，我们预测HA在心肌梗死后具有动态作用。 失败：早期有益，晚期适应不良。总之，这些研究将提供新的见解的作用 HA在胶原分泌、急性瘢痕形成和慢性纤维化中的作用。有了这些基本知识，我们 可以在未来的研究中探索治疗方法。不管这项研究计划的具体结果如何， 这个奖学金将作为一个很好的工具，以加强我的培训，使我最终能够成为一个 独立科学家领导我自己的研究实验室。结合实验方案， 实验工具，我的赞助商，环境，先进的课程，和专业发展 机会为我实现最终目标创造了很大的可能性，并为我的未来做出了重大贡献。 过程中的文学。

Project Abstract The extracellular matrix (ECM) provides structural and functional support for the myocardium; however, heart failure alters the composition of the ECM. The ECM is composed of a number of proteins, lipids, and saccharides, yet their function is largely unknown. We found that one of the most abundant components of the ECM, hyaluronan (HA), accumulates following myocardial infarction; however, the role of HA following during infarct- induced heart failure is not known. Fibroblasts are a major cell type involved in ventricular remodeling. Once activated, fibroblasts proliferate and produce ECM components, such as collagen and HA. These events are associated with acute scar formation and chronic ventricular remodeling. In this project, I will explore the extent to which fibroblast-derived HA impacts the extracellular matrix. Specifically, I will study fibroblasts collagen secretion when HA metabolism is manipulated. Additionally, I will examine the extent to which fibroblast-derived HA contributes to acute scar formation post-MI. Finally, I will determine the extent to which fibroblast-derived hyaluronan contributes to chronic ventricular remodeling. We contend that acute increases in HA accumulation are required for scar formation following acute MI; however, the persistent, excessive production of HA provokes fibrosis beyond the initial scar. Hence, we predict that HA has a dynamic role following infarct-induced heart failure: beneficial early and maladaptive late. Taken together, these studies will provide novel insight into the role of HA in collagen secretion, acure scar formation, and chronic fibrosis. With this fundamental knowledge, we can, in future studies, explore therapeutic approaches. Regardless of the specific findings of this research plan, this fellowship will serve as an excellent vehicle to enhance my training so I can eventually become an independent scientist leading my own research laboratory. The combination of the experimental plan, experimental tools, my sponsor, the environment, advanced coursework, and professional development opportunities creates a high likelihood for me to realize my eventual goals and contribute significantly to the literature in the process.