Grant: Operating Grant

High density lipoproteins are called "good cholesterol" because high levels of HDL in blood protect against heart disease. This protection is partly due to the ability of HDL to prevent the accumulation of fat that clogs arteries and leads to heart attacks and stroke. The research we are proposing in this application aims to understand how HDL interacts with cells in the artery wall to bring about this protection. We are proposing to analyze the molecular events that are triggered by the interaction of HDL with different cells in the artery wall, and will test the roles of some of the cellular machinery that is either involved in the interaction or which is activated by it. We will then test the roles of the key cellular factors in a unique mouse model of coronary artery disease and heart attack. These mice lack the HDL receptor and develop blocked coronary arteries and heart attack when fed a high fat diet. We showed that we can prevent this by transplanting stem cells containing the intact HDL receptor gene--these stem cells go on to give rise to all blood cells including macrophages, which play a key role in the formation of blocked arteries. This model system will allow us to test the roles of other genes that might be involved in this pathway, downstream of the HDL receptor. The results from this study will give us important information on the molecular and cellular pathways that underlie how HDL protects against hardening of the arteries and will lead to new targets for drug development and new ideas for treatment of disease in humans.