Extracellular Matrix Dynamics During Remodeling

重塑过程中的细胞外基质动力学

• 批准号: 10585919
• 负责人: Steven P Jones
• 金额: $ 54.57万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10585919
• 关键词: Abate; Acute; Anabolism; Attention; Binding; Biomechanics; CD44 Antigens; Cardiac; Cardiac Myocytes; Catabolism; Cells; Chronic; Chronic Phase; Cicatrix; Collagen; Collagen Fibril; Complex; Congestive Heart Failure; Coupled; Data; Dependence; Deposition; Disease; Embryo; Enzymes; Event; Extracellular Matrix; Family; Fibroblasts; Fibrosis; Glucose; Glycolysis; HAS2 gene; Heart; Heart failure; Hyaluronan; Hyaluronidase; Impairment; Inflammation; Inflammatory; Investigation; Knowledge; Leukocytes; Macrophage; Matrix Metalloproteinases; Mediating; Mesenchymal; Metabolic; Metabolism; Mus; Myeloid Cells; Myocardial Infarction; Outcome; Pathologic; Pathology; Pathway interactions; Phase; Population; Process; Production; Proliferating; Proxy; Regulation; Role; Shapes; Testing; Tissues; Ventricular Function; Ventricular Remodeling; cell type; gain of function; glucose metabolism; hyaluronan synthase 1; insight; loss of function; metabolomics; migration; response to injury; stable isotope; wound healing

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.

项目摘要 对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。虽然这样的研究为纤维状纤维提供了大量的见解 在细胞外基质(ECM)的变化方面，很少有人关注血管内皮细胞的非纤维成分 ECM。事实上，ECM是由许多可溶的和受约束的因素组成的。这些不同ECM的作用 成分多种多样，但基本上是未知的。此外，这些因素如何与现有的实质相互作用 细胞，间充质细胞的变化和扩大的群体，以及暂时性的白细胞，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 仍然是原始的。事实上，细胞外基质中含量最丰富的成分之一--透明质酸(HA)具有 在很大程度上是通过神秘或推定的机制。透明质酸最终来源于葡萄糖，由一种 一类酶，称为透明质酸合成酶(HAS)。HA的作用在整个过程中可能动态地不同 改建。我们的初步数据表明，HA在心肌梗死后早期在心脏内积聚 (MI)，并在MI后持续数周的积累。我们还表明，急性激活的成纤维细胞有助于 到HA生产。鉴于心肌梗死后透明质酸积聚迅速，活化的成纤维细胞可增加透明质酸 产生，这表明成纤维细胞-HA轴在急性瘢痕形成中的潜在作用。然而，执着的 HA的积聚可能引发巨噬细胞依赖的炎症，并促进不利的重塑 在伤疤成熟后。我们的初步数据显示，HA直接损害巨噬细胞的功能，从而 可能是心脏重塑中未消退炎症的基础。我们假设，房委会在 急性心肌梗死后环境与慢性心力衰竭构成主要的、未被评估的脑室事件 改建。这暗示HA既不是纯粹的病理性，也不是纯粹的适应性。相反，房委会的角色是 取决于上下文。因此，我们必须了解心脏衰竭时产生HA的规律。 我们假设在急性心肌梗死后，成纤维细胞利用代谢变化产生更多的HA，并有助于 瘢痕的形成；然而，HA的不可阻挡的积累可能转变为在 慢性期。在这个项目的过程中，我们将使用一组功能的增益和损耗 检验成纤维细胞葡萄糖代谢变化驱动透明质酸的中心假说的方法 生产，它强烈地帮助形成疤痕，但慢性延长炎症和促进不良反应 改建。无论具体结果如何，这个项目的完成都将创造出根本的、机械性的 对心室重塑过程中细胞外基质变化的原因和后果的洞察。