Our long-term goal is to establish the structural features responsible for the cardioprotective functions of HDL in humans, which may have important implications for predicting CVD risk and developing HDL-targeted therapeutics. We have recently shown that apolipoprotein A1 (APOA1), HDL?s major apolipoprotein, can assume three different antiparallel isomeric structures we term rotamers. Strong preliminary data suggests that the different rotamers exist in humans, and that they affect HDL size and ability to bind different proteins, and have different abilities to promote cholesterol efflux from macrophages by the ABCA1 pathway. To determine the physiological relevance of the APOA1 rotamers, we therefore propose two specific aims. First, we will engineer Apoa1-/- mice to express mutated forms of human APOA1 that cause HDL to selectively form specific rotamers of APOA1 in vivo. We will then determine the impact of the different rotamers on HDL cholesterol efflux capacity, HDL size, HDL protein cargo, and atherosclerosis in LDL receptor-deficient mouse models. Second, we will complement our animal studies with analyses of HDLs of humans with and without carotid atherosclerotic disease, and with and without diabetes. We will determine whether the distribution of specific rotamers, HDL subspecies, and HDL protein cargo associate with cholesterol efflux capacity and whether they associate with or predict atherosclerotic disease in these subjects. Because preliminary studies show that HDL of diabetic patients have impaired cholesterol efflux capacity, and diabetic patients are at greatly increased risk of cardiovascular disease, our proposed investigation of the structural features of HDL that associate with both impaired HDL function and atherosclerotic disease could provide important insights into HDL-associated factors that are cardioprotective but are independent of HDL cholesterol levels.

Public Health Relevance

Our research centers on understanding the factors that control the ability of HDL -the good form of cholesterol- to inhibit atherosclerosis, the leading cause of heart disease in the US. Our studies focus on the structural features of HDL, and how differences in structures affect HDL function. Our long-term goals are to establish new HDL metrics to predict the risk of heart disease in humans and identify potential mechanisms for HDL- targeted therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL149685-01
Application #
9859254
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Liu, Lijuan
Project Start
2019-12-15
Project End
2023-11-30
Budget Start
2019-12-15
Budget End
2020-11-30
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195