Triglycerides, Diabetes and Cardiovascular Disease

The overall hypothesis of the Triglycerides, Diabetes and Cardiovascular Disease Program Project for the next 5 years is that that abnormal assembly, secretion, composition and clearance of TRLs promotes the accumulation of highly atherogenic RLPs in atherosclerotic lesions in individuals with T2D, and that RLPs contribute to CVD risk by altering lesion cell populations and functions, thereby increasing atherosclerotic lesion progression and hindering regression. We propose that the increased risk of cardiovascular disease (CVD) associated with diabetes can be understood, prevented, and treated only by increasing our knowledge of the factors that regulate triglyceride-rich lipoproteins (TRLs) and their remnant lipoprotein particles (RLPs). TRLs and their remnants comprise a great variety of nascent and metabolically derived particles differing in size, protein composition, and lipid content, which has made it difficult to identify the mechanisms that promote atherosclerosis. We plan to continue to address this complexity by focusing on specific pathways and proteins and by using unique analytical tools; building on the knowledge, methodology and tools we have accumulated in the current funding period. We believe that our highly interactive and interdisciplinary group of investigators with extensive expertise in this area is needed to answer the question of how TRLs and RLPs promote CVD risk. The expertise of our team in different aspects pertaining to the overall hypotheses of this Program Project will continue to ensure synergy and cross-fertilization between Projects, which is likely to markedly advance research in this important and timely area. Importantly, the RLPs and proteins that control them are amenable to therapeutic intervention. We therefore believe that our projects will continue to provide new insights into the pathogenesis of CVD in diabetes and suggest new ways to target and prevent the increased CVD risk in this large population. The Program Project Grant consists of three Projects and three Core units: • Project 1: Type 2 diabetes, APOC3 and cardiovascular disease – Karin E. Bornfeldt, PhD, Project Leader • Project 2: ANGPTL3-dependent mechanisms underlying adaptations in hepatic lipoprotein production and clearance – Nathan Stitziel, MD, PhD, Project Leader • Project 3: Triglycerides, lipolysis, and vascular inflammation – Ira J. Goldberg, MD, Project Leader • Core A: Administrative Core – Karin E. Bornfeldt, PhD, Core Director • Core B: Proteomics and lipoprotein characterization core – Tomas Vaisar, PhD, Core Director • Core C: Atherosclerosis and bioinformatics core – Jenny E. Kanter, PhD, Core Director