National Heart, Lung, and Blood Institute 5P01HL151328-07

Project 1. Type 2 diabetes, APOC3 and cardiovascular disease

NIH awarded $606,865 to University of Washington for research on the role of APOC3 in cardiovascular disease risk among type 2 diabetes patients, aiming to understand mechanisms and support future therapies.

Description

This project will clarify how myeloid cells govern hepatic secretion of APOC3-rich TRLs and how APOC3-rich TRLs affect lesional cell populations. The overall hypothesis is that lipid uptake by cell-bound triggering receptor expressed on myeloid cells 2 (TREM2) in myeloid cells protects hepatocytes from lipid overloading, increased production of APOC3-rich TRLs, and atherosclerosis, and that the adverse effects of APOC3 on lesional cell populations in T2D are mediated by APOC3-enriched TRLs. The project uses mechanistic mouse models of T2D with modulated TREM2 shedding to clarify effects on APOC3 kinetics and TRL production, assembly, and secretion. CITE-seq will be used on atherosclerosis lesions to elucidate how hepatic APOC3 silencing alters lesional cell populations. Studies on isolated smooth muscle and endothelial cells will reveal signaling pathways and cell functions regulated by hepatic APOC3. The project will also investigate whether soluble TREM2 predicts incident CVD events in humans with T2D and its link to APOC3. The goal is to provide insights into APOC3 mechanisms, supporting potential clinical trials to reduce CVD risk via APOC3-silencing therapy, especially in T2D subjects.

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