Fibroblast targeting for myocardial repair

成纤维细胞靶向心肌修复

• 批准号: 10636106
• 负责人: FRANCIS G SPINALE
• 金额: $ 67.18万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10636106
• 关键词: Ablation; Adverse effects; Animal Model; Animals; Cardiovascular Diseases; Cause of Death; Cells; Coronary Arteriosclerosis; Country; Development; Disease; Disease Progression; Encapsulated; Enzymes; Etiology; Extracellular Matrix; Extracellular Matrix Degradation; Family; Family suidae; Fibroblasts; Formulation; Gel; Gene Deletion; Health Expenditures; Heart; Heart failure; Hyaluronic Acid; Hydrogels; Injectable; Interruption; Knockout Mice; Laboratories; Left; Left Ventricular Remodeling; Left ventricular structure; Malignant Neoplasms; Membrane; Modeling; Molecular; Mus; Myocardial; Myocardial Infarction; Myocardium; Neoplasm Metastasis; Neoplasms; Normal tissue morphology; Outcome; Pathologic; Patients; Peptide Hydrolases; Performance; Phenotype; Play; Population; Prevention; Process; Proliferating; Protease Inhibitor; Recovery; Role; Secondary to; Shapes; Specificity; Structure; Support System; Testing; Therapeutic; Transgenic Organisms; Ventricular; cell type; conditional knockout; disability; fibroblast-activating factor; genetic signature; improved; inhibitor; minimally invasive; novel; novel therapeutics; particle; porcine model; prevent; protein activation; repaired; small molecule; small molecule therapeutics; tool; translational study

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.

摘要 心力衰竭（HF）仍然是死亡、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HF的主要原因。继发于MI的HF基本上是由于 左心室（LV）的结构和功能称为LV重构。病理 重塑，如癌症，侵袭性降解细胞类型的增殖， 出现癌相关成纤维细胞。癌相关成纤维细胞改变正常 通过细胞外基质（ECM）的降解/重塑改变组织结构。在 特别是蛋白水解酶成纤维细胞活化蛋白（FAP）的稳健表达。 我们已经确定，心肌梗死后成纤维细胞包含一个非常相似的蛋白水解签名， 作为癌症相关的成纤维细胞，在ECM降解和最终LV方面， 重塑因此，我们将测试FAP诱导/激活的指导假设， 是心肌梗死后不良重塑和进展为心力衰竭的关键， 在MI区域内局部靶向FAP是可行和有效的。的结局 这些转化研究将为建立一个全新的治疗方向， MI后心肌恢复和预防HF。我们已经建立了一个转基因 FAP条件性敲除小鼠系，其将允许MI后FAP沉默 诱导以及HF的发展。我们开发了独特的 允许释放小分子治疗剂的水凝胶制剂 蛋白酶抑制剂，已部署在我们的猪模型后MI使用最低限度的 侵入性方法。从这个项目的交付将是建立一个小说 预防和治疗继发于MI的HF的治疗方向 通过对FAP激活的时间和局部控制。这些结果将推动 通过建立成纤维细胞在HF中的作用， 通过利用新的分子工具和治疗方法， 特定的细胞表型在这种疾病的过程中。