Speaker
Description
Proteoforms - encompassing the diverse protein products arising from alternative splice isoforms, genetic variations, and posttranslational modifications (PTMs) originating from a single gene - are fundamental drivers in biology. Top-down mass spectrometry (MS)-based proteomics (TDP), analyzing whole proteins without digestion, offers a comprehensive perspective of proteoforms, which is invaluable in deciphering proteoform function, uncovering disease mechanisms, and advancing precision medicine. We have been developing novel technologies to address the challenges in top-down proteomics in a multi-pronged approach including new cleavable surfactants for protein solubilization, new strategies for multi-dimensional chromatography separation of proteins, novel nanomaterials for enrichment of low-abundance proteins. In this presentation, I will highlight the application of TDP to enable proteoform-resolved analysis of cardiac proteins directly from human heart tissues and human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs). Notably, we have identified altered cardiac proteoforms associated with contractile dysfunction. Through case studies in hypertrophic, ischemic, and dilated cardiomyopathy, we demonstrate how TDP uncovers disease mechanisms, reveals novel biomarkers, and informs therapeutic strategies. By mapping the proteoform landscape of the human heart, top-down proteomics has the potential to transform cardiovascular research and enable more precise, individualized interventions.
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