Leveraging Notch Signaling and Small Molecules in New Treatments for Myocardial Infarction
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Robeson, Matthew James
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Abstract
C-kit+ Cardiac progenitor cells have been widely investigated over the last two decades as a potential therapeutic for myocardial infarction (MI). While these cells were originally thought to contribute to the formation of new cardiomyocytes, we now know that CPCs are primarily and endothelial cell type. However, research from our lab and others has demonstrated that these cells still have a reparative benefit when implanted in vivo following MI, contributing to a reduction in fibrosis and revascularization around the infarct, primarily mediated by the release of paracrine factors including miRNA. Studies from our lab and others have demonstrated the importance of the highly conserved developmental signaling pathway known as Notch within these CPCs, but to present, an extensive study on the mechanistics of Notch signaling in the CPC niche has not been performed. By stimulating CPCs with each of the four canonical Notch ligands, I demonstrate changes in gene expression profile and cellular function that highlight the importance of ligand discrimination in Notch signaling in CPCs. Additionally, I develop an injectable hydrogel capable of stimulating Notch and show the potential benefits for implantation in an in vivo model of MI in a rat heart. I also investigated the striated muscle protein MG53 and its E3 ligase dead mutant MG53-C14A, a potential therapeutic for MI that provides provides protection against ischemic damage but also contributes to insulin resistance within the heart.
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2024-12-08
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Dissertation