This project seeks to identify novel inotropes to preserve contractile function following ischemic injury to the myocardium. Through the translational nature of this lab, much of our work goes into validating and synthesizing numerous pieces of existing literature to develop fully fledged therapeutics.

For the development of our inotrope, we are primarily interested in modulating the activity of the MARK4 kinase. This kinase is an upstream regulator of alpha-tubulin detyrosination, which is a post-translational modification that has been previously shown to positively associate with lessened contractile function of the left ventricle, consequently lowering the heart’s ejection fraction and threatening heart failure. There are numerous ways of targeting this pathway, whether it’s through antibodies or through targeting proteins more directly responsible for regulating alpha-tubulin detyrosination. However, we ultimately chose to inhibit MARK4 with biologics because of its cost-effectiveness, increased likelihood of potency, and ease of scalability.

Once we identified compounds with a more pronounced effect in vitro, their effect needed to be understood in organisms at the level of molecules, tissue, and organs. To do this, we needed to expand our armamentarium of analytical techniques and develop expertise in troubleshooting new methods and deriving meaning from new metrics. Some of the techniques we incorporated into this study are discussed in this poster, and include staining for apoptotic cell death, catheterization of the left ventricle to obtain pressure and volume metrics, and measuring scar tissue areas from cross-sectional stains of apical heart tissue. By using a variety of methods to confirm our findings, we can be certain that our conclusions are thoroughly justified and can be built on further.