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 TGF? binding to the TGF? receptor IIs (TGF?RIIs) on cardiac fibroblasts, are responsible for cardiac fibrosis. As such, to prevent cardiac fibrosis fro progressing, it is essential to inhibit the TGF? pathway-mediated new myofibroblast formation, and to convert existing myofibroblasts back to cardiac fibroblasts. Yet current preclinical approaches, such as the systemic delivery of TGF? inhibitors or anti-TGF? antibodies, only decrease the content of active TGF? in the heart, but do not inhibit the binding of TGF? to TGF?RIIs, thus cannot fundamentally prevent myofibroblast formation. Besides, the systemic delivery causes dose-limiting side effects. While the use of TGF?RII inhibitors have the potential to prevent myofibroblast formation by blocking TGF? from binding to TGF?RIIs, 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 TGF?RII inhibitor, and its delivery system to efficiently inhibit TGF? 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 TGF?RII inhibitor ECG. It blocks the initial step of the TGF? pathway ? TGF? binding to TGF?RIIs. It specifically binds to the TGF?RIIs on cardiac fibroblasts without differentiating them into myofibroblasts. ECG also has a higher affinity for TGF?RIIs than TGF?. Therefore, once the ECG binds to TGF?RIIs, TGF? cannot bind to these receptors. ECG also pulls off those TGF? already bonded to TGF?RIIs and occupies the receptors by itself. As a result, ECG is able to prevent TGF?-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.

Public Health Relevance

Continued cardiac fibrosis leads to progressive deterioration of cardiac function, and advances infarcted hearts towards heart failure. Yet the ideal therapeutic strategies to control cardiac fibrosis remain to be established. Accomplishment of the proposed research will create a novel drug delivery system to inhibit cardiac fibrosis from progressing at different stages of post myocardial infarction, thus preventing cardiac function from progressive deterioration.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
5R01EB022018-02
Application #
9280949
Study Section
Biomaterials and Biointerfaces Study Section (BMBI)
Program Officer
Hunziker, Rosemarie
Project Start
2016-06-01
Project End
2019-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
2
Fiscal Year
2017
Total Cost
$674,848
Indirect Cost
$181,028
Name
Ohio State University
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Fan, Zhaobo; Xu, Zhaobin; Niu, Hong et al. (2018) An Injectable Oxygen Release System to Augment Cell Survival and Promote Cardiac Repair Following Myocardial Infarction. Sci Rep 8:1371
Shah, Mickey; Kc, Pawan; Copeland, Katherine M et al. (2018) A Thin Layer of Decellularized Porcine Myocardium for Cell Delivery. Sci Rep 8:16206
Zhu, Qingxia; Li, Xiaofei; Fan, Zhaobo et al. (2018) Biomimetic polyurethane/TiO2 nanocomposite scaffolds capable of promoting biomineralization and mesenchymal stem cell proliferation. Mater Sci Eng C Mater Biol Appl 85:79-87
Chen, Joseph; Brazile, Bryn; Prabhu, Raj et al. (2018) Quantitative Analysis of Tissue Damage Evolution in Porcine Liver With Interrupted Mechanical Testing Under Tension, Compression, and Shear. J Biomech Eng 140:
Fan, Zhaobo; Fu, Minghuan; Xu, Zhaobin et al. (2017) Sustained Release of a Peptide-Based Matrix Metalloproteinase-2 Inhibitor to Attenuate Adverse Cardiac Remodeling and Improve Cardiac Function Following Myocardial Infarction. Biomacromolecules 18:2820-2829
Li, Chuan; Matsushita, Satoshi; Li, Zhengqing et al. (2017) c-kit Positive Cardiac Outgrowth Cells Demonstrate Better Ability for Cardiac Recovery Against Ischemic Myopathy. J Stem Cell Res Ther 7:
Li, Zhenqing; Fan, Zhaobo; Xu, Yanyi et al. (2016) Thermosensitive and Highly Flexible Hydrogels Capable of Stimulating Cardiac Differentiation of Cardiosphere-Derived Cells under Static and Dynamic Mechanical Training Conditions. ACS Appl Mater Interfaces 8:15948-57