Person:
Davis, Michael E.

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https://hdl.handle.net/1853/71196
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High-Throughput Screening Identifies Micrornas That Target Nox2 and Improve Function Following Acute Myocardial Infarction

2017-02-24 , Yang, Junyu , Brown, Milton E. , Zhang, Hanshuo , Martinez, Mario , Zhao, Zhihua , Bhutani, Srishti , Yin, Shenyi , Trac, David , Xi, Jianzhong Jeff , Davis, Michael E.

Myocardial infarction (MI) is the most common cause of heart failure. Excessive production of reactive oxygen species plays a key role in the pathogenesis of cardiac remodeling after MI. NADPH with Nox2 as the catalytic subunit is a major source of superoxide production and expression is significantly increased in the infarcted myocardium, especially by infiltrating macrophages. While microRNAs (miRNAs) are potent regulators of gene expression, and play an important role in heart disease, there still lacks efficient ways to identify miRNAs that target important pathological genes for treating MI. Thus, the overall objective was to establish a miRNA screening and delivery system for improving heart function after MI using Nox2 as a critical target.

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Controlled delivery of PDGF-BB, and endothelial-derived cardiomyocyte survival factor, for myocardial protection using injectable self-assembling peptide nanofibers

2006-01 , Hsieh, Patrick C.H. , Davis, Michael E. , Gannon, Joseph , MacGillivray, Catherine , Lee, Richard T.

Endothelial cells can protect cardiomyocytes from injury, but the mechanism of this protection is incompletely described. Here we demonstrate that protection of cardiomyocytes by endothelial cells occurs through PDGF-BB signaling. PDGF-BB induced cardiomyocyte Akt phosphorylation in a time- and dose-dependent manner and prevented apoptosis via PI3K/Akt signaling. Using injectable self-assembling peptide nanofibers, which bound PDGF-BB in vitro, sustained delivery of PDGF-BB to the myocardium at the injected sites for 14 days was achieved. A blinded and randomized study in 96 rats showed that injecting nanofibers with PDGF-BB, but not nanofibers or PDGF-BB alone, decreased cardiomyocyte death and preserved systolic function after myocardial infarction. A separate blinded and randomized study in 52 rats showed that PDGF-BB delivered with nanofibers decreased infarct size after ischemia/reperfusion. PDGF-BB with nanofibers induced PDGFR-β and Akt phosphorylation in cardiomyocytes in vivo. These data demonstrate that endothelial cells protect cardiomyocytes via PDGF-BB signaling and that this in vitro finding can be translated into an effective in vivo method of protecting myocardium after infarction. Furthermore, this study shows that injectable nanofibers allow precise and sustained delivery of proteins to the myocardium with potential therapeutic benefits.

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Novel Strategies for Treating Cardiac Dysfunction

2010-10-12 , Davis, Michael E.

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Custom design of the cardiac microenvironment with biomaterials

2005-07 , Davis, Michael E. , Hsieh, Patrick C.H. , Grodzinsky, Alan J. , Lee, Richard T.

Many strategies for repairing injured myocardium are under active investigation, with some early encouraging results. These strategies include cell therapies, despite little evidence of long-term survival of exogenous cells, and gene or protein therapies, often with incomplete control of locally-delivered dose of the factor. We propose that, ultimately, successful repair and regeneration strategies will require quantitative control of the myocardial microenvironment. This precision control can be engineered through designed biomaterials that provide quantitative adhesion, growth, or migration signals. Quantitative timed release of factors can be regulated by chemical design to direct cellular differentiation pathways such as angiogenesis and vascular maturation. Smart biomaterials respond to the local environment, such as protease activity or mechanical forces, with controlled release or activation. Most of these new biomaterials provide much greater flexibility for regenerating tissues ex vivo, but emerging technologies like self-assembling nanofibers can now establish intramyocardial cellular microenvironments by injection. This may allow percutaneous cardiac regeneration and repair approaches, or injectable-tissue engineering. Finally, materials can be made to multifunction by providing sequential signals with custom design of differential release kinetics for individual factors. Thus, new rationally-designed biomaterials no longer simply coexist with tissues, but can provide precision bioactive control of the microenvironment that may be required for cardiac regeneration and repair.

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Novel Strategies for Treating Myocardial Infarction

2010-05-27 , Davis, Michael E.

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