Maladaptive Remodeling in Aging Myocardium

左心室（LV）重塑是细胞和细胞外基质（ECM）事件的总和， 其总是发生在心肌梗死（MI）之后，并且是临床预后的重要预测因子。 结果。ECM蛋白水解酶、基质金属蛋白酶的诱导增加 MMPs（基质金属蛋白酶）发生在心肌梗死后重塑的早期和晚期。虽然MMP抑制仍然是一种有效的方法， 心肌梗死后重塑背景下的重要治疗靶点，全身递送广谱 药物MMP抑制剂可能与不良事件相关，这些问题与 给药方案的困难阻碍了临床进展。在我们过去的表演中 在此期间，我们成功地推动了该领域的发展，证明了本地化交付 透明质酸基水凝胶（HA-凝胶）的释放和MMP抑制肽的释放可以 有效地减轻了心肌梗死后的不良重塑。我们现建议进一步推动 这些概念验证研究和“再利用”MMP抑制剂的转化和临床相关性 通过克服过去关于全身递送的障碍而在临床上取得了进展， 的特异性我们的指导假设是，使用一种新的自组装HA凝胶，它将释放一种 药物MMP抑制剂选择性地进入MI区域，将有效地和有利地改变MI区域的功能。 心肌梗死后不良重塑的过程。我们先确定局部注射透明质酸- 凝胶/MMP抑制剂构建体将降低局部MMP活性，减弱MI后局部MMP活性， 重塑和成纤维细胞转分化，从而防止LV泵的进展 失败接下来，我们将证明HA-凝胶/MMP抑制剂构建体的靶向注射将 对MI后重塑的自然史产生有利影响，无论是早期还是晚期注射 心梗后最后，我们将通过展示这些研究的翻译相关性， HA-凝胶/MMP抑制剂构建体使用新的递送方法的有益效果。这些研究 将提供关键的临床前信息，以进一步推进 局部MMP抑制控制，以中断不利LV的不可阻挡的进展 心肌梗死后重塑和随后的心力衰竭。

Left ventricular (LV) remodeling is a summation of cellular and extracellular matrix (ECM) events, which invariably occur following a myocardial infarction (MI) and is an important predictor of clinical outcomes. Increased inductions of the ECM proteolytic enzymes, the matrix metalloproteinases (MMPs), occur in the early and late phases of post-MI remodeling. While MMP inhibition remains an important therapeutic target in the context of post-MI remodeling, systemic delivery of broad spectrum pharmacologic MMP inhibitors can be associated with adverse events, and these concerns coupled with difficulties in dosing regimens have hindered clinical progress. During our past performance period, we have successfully moved the field forward in terms of demonstrating that localized delivery of a hyaluronic acid based hydrogel (HA-gel) and release of an MMP inhibitory peptide could effectively attenuate adverse post-MI remodeling. We now propose to further advance the translational and clinical relevance of these proof of concept studies and “repurpose” MMP inhibitors that were advanced clinically by overcoming past obstacles regarding systemic delivery and specificity. Our guiding hypothesis is that using a novel self-assembling HA-gel, which will release a pharmacological MMP inhibitor selectively into the MI region, will effectively and favorably alter the course of adverse post-MI remodeling. We will first establish that localized injection of an HA- gel/MMP inhibitor construct will reduce regional local MMP activity, attenuate post-MI regional remodeling and fibroblast transdifferentiation, and thereby prevent the progression of LV pump failure. Next, we will demonstrate that targeted injection of an HA-gel/MMP inhibitor construct will cause favorable effects on the natural history of post-MI remodeling, whether injected early or late post-MI. Finally, we will advance the translational relevance of these studies by demonstrating the beneficial effects of the HA-gel/MMP inhibitor construct using novel delivery methods. These studies will provide the pivotal pre-clinical information in order to further advance the therapeutic avenue of localized MMP inhibitory control in order to interrupt the inexorable progression of adverse LV remodeling post-MI and subsequent heart failure.