Control of cardiac fibrosis to prevent cardiac function deterioration

 描述：心肌梗死(MI)后自然会出现心脏纤维化。虽然形成的纤维化组织最初保护心脏免受破裂，但持续的心脏纤维化导致心脏功能进行性下降，并使梗塞的心脏走向心力衰竭。因此，一种可以抑制心肌梗死后不同阶段的心脏纤维化进展的治疗方法将保护心脏功能，防止心脏演变为心力衰竭。然而，目前还没有临床批准的治疗方法。心肌成纤维细胞主要通过转化生长因子β与心脏成纤维细胞上的转化生长因子β受体II(转化生长因子β受体)结合而形成，参与心肌纤维化的形成。因此，为了防止心肌纤维化的进展，有必要抑制转化生长因子β途径介导的新的肌成纤维细胞的形成，并将现有的肌成纤维细胞转化为心脏成纤维细胞。然而，目前的临床前方法，如全身应用转化生长因子β抑制剂或抗转化生长因子β抗体，仅能降低心脏中活性转化生长因子β的含量，而不能抑制转化生长因子β与转化生长因子β的结合，因此不能从根本上阻止肌成纤维细胞的形成。此外，全身给药还会产生剂量限制的副作用。而使用转化生长因子βRII抑制剂具有潜在的 为了通过阻断转化生长因子β与转化生长因子β的结合来阻止肌成纤维细胞的形成，大多数药物由于有效剂量一直高于毒性水平而不适合心脏抗纤维化治疗。本项目的基本目标是创造一种基于多肽的、低毒的转化生长因子βRII抑制剂及其递送系统，以有效地抑制转化生长因子β途径介导的心肌纤维化在心肌梗死后不同阶段的进展，从而防止心功能的进行性恶化。在我们的初步研究中，我们创造了一种基于多肽的转化生长因子βRII抑制剂心电。它阻断了转化生长因子β途径的第一步-转化生长因子β与转化生长因子βRiis的结合。它能与心脏成纤维细胞上的转化生长因子β核糖核酸特异结合，但不能分化为肌成纤维细胞。ECG对转化生长因子β的亲和力也高于转化生长因子β。因此，一旦心电信号与转化生长因子β结合，转化生长因子β就不能与这些受体结合。心电信号还可取出已与转化生长因子β结合的转化生长因子β，并自行占据受体。因此，心电可以阻止转化生长因子β诱导的肌成纤维细胞分化，并使肌成纤维细胞恢复为心脏成纤维细胞。为了在不引起剂量限制的副作用的情况下将心电信号输送到梗死心脏，我们开发了一种可注射的快速凝胶水凝胶，可以特异性地注射到梗死心脏，注射后能迅速凝固(&lt；10 S)，有效地将心电信号保留在心脏中，并能逐渐释放心电信号。我们的初步体内研究表明，基于水凝胶的心电释放系统可以减轻心肌纤维化。基于上述研究，我们假设局部注射水凝胶为基础的心电释放系统将显著减轻心肌梗死后不同阶段的心肌纤维化，从而防止心功能的进行性恶化。这一假设将通过两个特定的目标进行检验：目标1将检验这样一个假设，即最佳的心电释放谱将有效地阻止心脏成纤维细胞分化为肌成纤维细胞，并将肌成纤维细胞转化为心脏成纤维细胞。目的#2将验证这一假设，即心电信号释放系统将在心肌梗死后不同阶段抑制心肌梗死心脏纤维化的进展，以防止心功能进行性恶化。

 DESCRIPTION: Cardiac fibrosis naturally occurs following myocardial infarction (MI). While the fibrotic tissue that forms initially protects the heart from rupture, continued cardiac fibrosis leds to a progressive decrease in cardiac function, and advances the infarcted heart towards heart failure. Accordingly, a therapy that can inhibit cardiac fibrosis from progressing at different stages of post-MI will preserve cardiac function and prevent the heart from evolving towards heart failure. However, there is currently no clinically approved therapy available. Myofibroblasts, formed primarily through TGFβ binding to the TGFβ receptor IIs (TGFβRIIs) on cardiac fibroblasts, are responsible for cardiac fibrosis. As such, to prevent cardiac fibrosis fro progressing, it is essential to inhibit the TGFβ pathway-mediated new myofibroblast formation, and to convert existing myofibroblasts back to cardiac fibroblasts. Yet current preclinical approaches, such as the systemic delivery of TGFβ inhibitors or anti-TGFβ antibodies, only decrease the content of active TGFβ in the heart, but do not inhibit the binding of TGFβ to TGFβRIIs, thus cannot fundamentally prevent myofibroblast formation. Besides, the systemic delivery causes dose-limiting side effects. While the use of TGFβRII inhibitors have the potential to prevent myofibroblast formation by blocking TGFβ from binding to TGFβRIIs, most of them are not suitable for cardiac anti-fibrotic therapy due to the effective dosages being always above the toxic level. The fundamental goal of this project is to create a peptide-based, low toxicity TGFβRII inhibitor, and its delivery system to efficiently inhibit TGFβ pathway-mediated cardiac fibrosis from progressing at different stages of post-MI, thus preventing cardiac function from progressive deterioration. In our preliminary studies, we have created a peptide based TGFβRII inhibitor ECG. It blocks the initial step of the TGFβ pathway ‒ TGFβ binding to TGFβRIIs. It specifically binds to the TGFβRIIs on cardiac fibroblasts without differentiating them into myofibroblasts. ECG also has a higher affinity for TGFβRIIs than TGFβ. Therefore, once the ECG binds to TGFβRIIs, TGFβ cannot bind to these receptors. ECG also pulls off those TGFβ already bonded to TGFβRIIs and occupies the receptors by itself. As a result, ECG is able to prevent TGFβ-induced myofibroblast differentiation, and revert myofibroblasts back to cardiac fibroblasts. To deliver ECG into infarcted hearts with high ECG retention in the tissue, and without causing dose-limiting side effects, we have developed an injectable and fast gelation hydrogel that can be specifically injected into infarcted hearts, can quickly solidify (<10 s) afte injection to efficiently retain ECG in the heart, and can gradually release ECG. Our preliminary in vivo study demonstrated that the hydrogel-based ECG release system attenuated cardiac fibrosis. Based on the above studies, we hypothesize that local delivery of hydrogel-based ECG release system into the infarcted heart will significantly attenuate cardiac fibrosis at different stages of post-MI, thus preventing cardiac function from progressive deterioration. The hypothesis will be tested through 2 specific aims: AIM #1 will test the hypothesis that optimal ECG release profiles will efficiently prevent cardiac fibroblasts from differentiating into myofibroblasts, and convert myofibroblasts back to cardiac fibroblasts. AIM #2 will test the hypothesis that ECG release systems will inhibit cardiac fibrosis from progressing in the infarcted hearts at different stages of post-MI to prevent progressive cardiac function deterioration.