Low levels of high-density lipoprotein (HDL) are a major risk factor for developing cardiovascular disease (CVD). We have uncovered defective trafficking of the ABCA1 cholesterol transporter as a major cause of low HDL. Furthermore, we have shown that ABCA1 trafficking can be restored with the chemical chaperone, 4-phenylbutyrate (4-PBA), although the mechanism is unknown. We aim to identify the molecules involved in the restoration of ABCA1 trafficking by 4-PBA and to identify new molecules and genes that regulate HDL production. We will use cell biology and proteomic approaches as well as new DNA sequencing technology to achieve this. Outcomes include a potential new ""HDL increasing therapy,"" which could lead to clinical trials as well as the identification of new targets for manipulating HDL levels. Our research could lead to better management of lipid risk factors and a reduction in CVD risk for many people.