Project Summary/Abstract Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in chronic kidney disease (CKD), reducing the life expectancy of CKD and dialysis patients to roughly half to one-third that of the general population. However, the pathogenesis of the accelerated CVD in CKD is not yet clearly understood, and no specific therapeutic strategies are currently available to attenuate this phenomenon. Our long-term goal is to understand the mechanisms underlying accelerated atherosclerosis in order to develop diagnostic and therapeutic solutions to improve the lifespan of patients with CKD. Our overall objective is to define the role of myeloperoxidase in the pathophysiology of CKD atherosclerosis. Our central hypothesis is that the myeloperoxidase oxidized HDL accelerates cardiovascular disease in CKD. Our rationale is that if myeloperoxidase oxidized HDL accelerates CKD atherosclerosis, then we can develop new therapeutic strategies and biomarkers to attenuate the CVD burden in the CKD population. We will test our central hypothesis by demonstrating the role of myeloperoxidase oxidation on the efflux capacity, HDL proteome, and incident CVD events in CKD patients. We will delineate the extent of myeloperoxidase-based oxidation of HDL using mass spectrometry in 348 patients of the RRI-CKD and test their ability to predict CVD events. We also evaluate the effect of myeloperoxidase oxidized HDL on cholesterol efflux capacity and the HDL proteome. This project was delayed by the multiple lab closures and core staff delays caused by the COVID-19 pandemic. Support from the NHLBI for continued protected time and salary will ensure this project's completion and help establish Dr. Mathew's research independence. The proposed research is innovative in that it links myeloperoxidase oxidation of the HDL proteome to accelerated CVD in CKD via mass spectrometric metabolic profiling and HDL proteomics. The proposed research is significant because it will provide strong evidence of the role of myeloperoxidase oxidized HDL in the pathogenesis and prediction of CVD in CKD patients, potentially leading to clinical studies to prevent CV events in CKD atherosclerosis.