Extracellular Matrix Dynamics During Remodeling

项目摘要 心室重构的研究几乎完全集中在胶原沉积的变化上 和基质金属蛋白酶活性。虽然这些研究提供了许多关于纤维状的见解， 细胞外基质（ECM）的变化，很少注意到细胞外基质的非纤维成分。 ECM。事实上，ECM由许多可溶性和结合因子组成。这些不同ECM的作用 成分多种多样，但大部分未知。此外，这些因素如何与现有的实质 细胞，间充质细胞的变化和扩增群体，以及短暂的白细胞，如 巨噬细胞，仍需仔细检查。尽管ECM很复杂，但我们对它的理解 保持原始状态。事实上，ECM中最丰富的成分之一透明质酸（HA） 通过很大程度上神秘或推测的机制。最终衍生自葡萄糖，HA由 酶家族，称为透明质酸合酶（HAS）。HA的角色在整个过程中可能动态地不同 重塑我们的初步数据表明，HA在心肌梗死后早期积聚在心脏中 (MI)并且其积累在MI后持续数周。我们还表明，急性激活的成纤维细胞有助于 HA生产。鉴于HA在MI后迅速积聚，活化的成纤维细胞可增加HA 这表明成纤维细胞-HA轴在急性瘢痕形成中的潜在作用。但坚持的 HA的积累可能引起巨噬细胞依赖性炎症，并导致不良重塑 在疤痕成熟后我们的初步数据表明，HA直接损害巨噬细胞功能， 可能是重塑心脏中未消退的炎症的基础。我们明白，医管局在 急性心肌梗死后与慢性心力衰竭相比， 重塑这暗示HA既不是纯病理性的，也不是纯适应性的。相反，医管局的角色是 上下文相关。基于这些原因，我们必须了解衰竭心脏中HA产生的调节。 我们证实，急性心肌梗死后，成纤维细胞利用代谢变化产生更多的HA，并有助于 瘢痕形成;然而，HA的不可阻挡的积累可能转变为病理学的贡献者， 慢性阶段。在本项目的过程中，我们将使用一组功能获得和功能丧失 检验成纤维细胞葡萄糖代谢变化驱动透明质酸的中心假设的方法 生产，这急性艾滋病的疤痕形成，但慢性炎症，并促进不利的 重塑不管具体结果如何，完成这个项目将从根本上， 深入了解心室重塑过程中细胞外基质变化的原因和后果。

Project Summary Investigations of ventricular remodeling have focused almost exclusively on changes in collagen deposition and matrix metalloproteinase activity. While such investigations have provided numerous insights into fibrillar changes in the extracellular matrix (ECM), little attention has been paid to the non-fibrillar components of the ECM. Indeed, the ECM is composed of numerous soluble and bound factors. The roles of these various ECM components are diverse, but largely unknown. Moreover, how these factors interact with existing parenchymal cells, the changing and expanding populations of mesenchymal cells, and the transitory leukocytes, such as macrophages, remains to be examined carefully. Despite the complexity of the ECM, our understanding of it remains primitive. In fact, one of the most abundant components of the ECM, hyaluronan (HA), functions through largely cryptic or presumed mechanisms. Ultimately derived from glucose, HA is synthesized by a family of enzymes, known as hyaluronan synthases (HAS). The role of HA may differ dynamically throughout remodeling. Our preliminary data indicate that HA accumulates in the heart early after a myocardial infarction (MI) and its accumulation persists for weeks after MI. We also show that acutely activated fibroblasts contribute to HA production. Given that HA accumulates quickly following MI and activated fibroblasts can increase HA production, this suggests a potential role for a fibroblast-HA axis in acute scar formation. Yet, the persistent accumulation of HA may provoke macrophage-dependent inflammation and contribute to adverse remodeling after the scar has matured. Our preliminary data show that HA directly impairs macrophage function, which may underlie non-resolving inflammation in the remodeling heart. We posit that the changing roles of HA in the acute post-MI setting versus chronic heart failure comprise major, unappreciated events in ventricular remodeling. This insinuates that HA is neither purely pathologic nor purely adaptive. Rather, the role of HA is context dependent. For these reasons, we must understand the regulation of HA production in the failing heart. We posit that acutely after MI, fibroblasts leverage metabolic changes to produce more HA and contribute to scar formation; however, the inexorable accumulation of HA may transition into a contributor to pathology in the chronic phases. Over the course of this project, we will use a battery of gain- and loss-of-function approaches to test the central hypothesis that changes in fibroblast glucose metabolism drive hyaluronan production, which acutely aids in scar formation but chronically prolongs inflammation and promotes adverse remodeling. Regardless of specific outcomes, completion of this project will create fundamental, mechanistic insights into the causes and consequences of changes in the extracellular matrix during ventricular remodeling.