Grant: Operating Grant

Heart disease is one of the leading causes of death in Canada. One of the best recognized risk factors for heart disease is high levels of low density lipoprotein cholesterol, or bad cholesterol. Our group is studying an enzyme found in circulation, called PCSK9 that helps to regulate bad cholesterol. When PCSK9 is very active it can cause cholesterol levels to rise, but when PCSK9 is less active it can decrease cholesterol levels so that individuals are protected from heart disease. We have recently observed that PCSK9 circulates in several molecular forms. We want to investigate whether these forms affect PCSK9 activity and therefore cholesterol levels. The amount of PCSK9 can change in response to hormones such as insulin. We want to investigate whether insulin can also change the molecular form and activity of PCSK9. We have recently observed that this enzyme, although found in both men and women, may be less active in women. This finding may contribute to why women are protected from heart disease in comparison to men. We believe one contributing factor may be the female hormone estrogen. Other groups have found that this hormone protects women from heart disease through several different means. We believe that this hormone may affect the action of PCSK9 in women. To find out if these lines of thinking are correct we want to use two different models, human liver cells in culture and mice. This study will lead to a better understanding of the functioning of PCSK9 in modifying cholesterol levels; it may also suggest new therapeutic approaches for the treatment of high cholesterol.