Harnessing Glycoproteomics and Glycomics to Understand Cardiac Biology and Disease

摘要

ABSTRACT Our research program develops and applies innovative mass spectrometry technologies, bioinformatics tools, and methodologies to transform our understanding of cell surface proteins and glycans and answer outstanding questions in stem cell biology and cardiac pathology. Our analytical platforms promote the development of new reagents and strategies to improve the quality and homogeneity of stem cell-derived cardiomyocytes for research and clinical applications and the discovery of strategies to monitor and treat patients with advanced heart failure. Specifically, our approaches enable the identification, characterization, and quantification of cell surface glycoproteins and glycans from small numbers of human cells. To date, we have developed new markers for identifying cardiomyocytes with high specificity and selecting maturation stage-specific stem cell derived cardiomyocytes to enable reproducible assessment and isolation of functionally-defined cells. Applying our technologies to primary human heart tissue, we have begun to develop cell-type specific views of the cell surface proteome and glycome within normal and failing hearts. We have also developed innovative bioinformatics tools to inform our next level of technology development to enhance our capabilities and improve the speed and accuracy with which we analyze our mass spectrometry data. The proposed studies build on these experiences to: 1) develop the next generation technology that will provide unparalleled specificity regarding the molecular phenotypes presented at the cell surface, information that is not possible to obtain by any current method, 2) develop marker panels that enable the assessment and selection of chamber- and maturation-stage specific stem cell derived cardiomyocytes without genetic editing, 3) define the cell-type specific receptors, membrane- bound ligands and secreted factors present in the normal human heart and how they change in disease to provide new understanding of intercellular signaling and inform the development of remote sensing markers to benefit the care of patients with advanced heart failure. The impact from the proposed studies lies within future applications and mechanistic studies that will be possible based on the approaches and data that we generate. As our program evolves to pursue mechanistic and translational studies of the molecules revealed by our discovery efforts, we expect the outcomes of these studies will broadly impact the development of strategies to improve the quality of stem cell derivatives to promote their utility for drug testing, disease modeling, and therapeutic applications, inform the development of cell-type directed payload delivery systems and drugs that avoid cardiotoxic effects, and yield new strategies to assess and treat advanced heart failure.