Fibroblast targeting for myocardial repair

摘要 心力衰竭仍然是导致死亡、残疾和健康的主要原因。 护理支出。冠状动脉疾病最终导致心肌梗死(MI) 仍然是心力衰竭的主要原因。心力衰竭继发于心梗的根本原因是 左心室(LV)的结构和功能称为LV重塑。在病理上 重塑，如癌症，侵袭性降解细胞类型的增殖， 癌症相关的成纤维细胞出现。癌症相关成纤维细胞改变正常 通过细胞外基质(ECM)的降解/重塑形成组织结构。在……里面 特别是，一种蛋白水解酶，成纤维细胞激活蛋白(FAP)的强势表达。 我们已经证实，心肌梗死后的成纤维细胞含有非常相似的蛋白分解特征。 作为癌症相关的成纤维细胞，在ECM降解和最终LV方面 改建。因此，我们将检验FAP诱导/激活的指导性假设 是心肌梗死后不良重塑和进展为心力衰竭的关键因素 在MI区域内定位FAP是可行和有效的。结果来自 这些转化研究将建立一个全新的治疗方向 心肌梗死后的心肌恢复及预防心力衰竭。我们已经建立了一种转基因 允许心肌梗死后FAP沉默的FAP条件性基因敲除小鼠品系 归纳和跟踪心力衰竭的发展。我们开发了独一无二的 水凝胶制剂，允许释放小分子治疗药物和 在我们的猪心肌梗死后模型中，已经使用了最低限度的 有侵入性的方法。这个项目的成果将是建立一个新的 心梗继发心力衰竭的防治方向 通过时间和局部控制FAP的激活。这些结果将会改变 通过建立成纤维细胞在心衰中的作用，使整个细胞外基质领域向前发展 利用新的分子工具和治疗方法靶向的全新方向 在此疾病过程中的特定细胞表型。

Abstract Heart failure (HF) continues to be a leading cause of death, disability and health care expenditures. Coronary artery disease culminating in a myocardial infarction (MI) remains a major cause for HF. HF secondary to MI is fundamentally due to changes in the structure and function of the left ventricle (LV) termed LV remodeling. In pathological remodeling such as cancer, the proliferation of an aggressive degradative cell type, the cancer associated fibroblast emerges. The cancer associated fibroblast alters normal tissue structure through degradation/remodeling of the extracellular matrix (ECM). In particular, a robust expression of a proteolytic enzyme, fibroblast activation protein (FAP). We have identified that the post-MI fibroblast contains a very similar proteolytic signature as the cancer associated fibroblast, in terms of ECM degradation and ultimately LV remodeling. Accordingly, we will test the guiding hypothesis that FAP induction/activation is essential for adverse post-MI remodeling and progression to HF and that specific localized targeting of FAP within the MI region is feasible and effective. The outcome from these translational studies will be to establish an entirely new therapeutic direction for myocardial recovery following MI and prevention of HF. We have established a transgenic line of FAP conditional knockout mice which will allow for FAP silencing following MI induction as well as following the development of HF. We have developed unique hydrogel formulations that allow for the release of small molecule therapeutics and protease inhibitors, which have been deployed in our pig model post-MI using a minimally invasive approach. The deliverables from this project will be to establish a novel therapeutic direction for the prevention as well as the treatment for HF secondary to MI through both temporal and localized control of FAP activation. These results will move the entire ECM field forward by establishing the role of the fibroblast in HF and open an entirely new direction through harnessing novel molecular tools and therapeutics to target specific cell phenotypes in this disease process.