Exploring the sepsis-delirium connection through glycoproteomics

Our proposal seeks to create and apply new glyco-proteomics procedures that permit unbiased discovery of alterations in protein glycosylation. This includes the creation of algorithms that assemble glycoproteoform networks from multi-dimensional mass spectrometry (MS) datasets, the prediction of underlying glycan information directly from intact glycoprotein MS spectral information, and statistical scoring with unique glycoproteoform informatics tools. An innovative aspect of the proposed technologies is that they are intended to permit evaluation of glycoproteins and prediction of glycan level information when glycosylation occurs at more than one amino acid residue, a well-recognized bottleneck in the top-down field. Our aims also include the application of the algorithms to enable unsupervised "discovery" of glycoproteoforms biomarkers in biofluids. We will use these new tools to monitor the blood-plasma/serum of patients that derive from the DECODE-SEPSIS and BRAIN-ICU programs with the intent to discover glycoproteoforms that correlate with specific endotypes or clinical symptoms that are associated with Sepsis spectrum disorders, including prediction of long-term cognitive dysfunction. In particular, we seek to establish unique datasets that can be used to inform upon sepsis that is tied to different anatomical regions or tied to complex mechanisms involved in both sepsis (endothelial dysfunction and inflammatory responses) and sepsis-adjacent (i.e. immunosuppression) events. Sepsis life-threatening, leading to organ dysfunction due to a dysregulated host response to infection and is an important global health problem that kills 11 million people each year many children, and disables millions more. In the United States, the CDC reports that sepsis, or the infection causing sepsis, starts outside the hospital in 87% of cases. These metrics highlight the urgent need for resources that can rapidly detect and stratify stages and mechanisms associated with individual patients. If our project aims are successful, we will not only have developed innovative new basic science tools for glycoscientists, but also, established innovative clinical proteomics procedures for the discovery and development of glycoprotein-based biomarkers intended to lay the groundwork for a unique datastream that is expected to provide unique insights into the variegated sepsis sup-phenotypes/endotypes.