Inhibition of c-Abl as a target for shortening glycosaminoglycan length on proteoglycans and preventing atherosclerosis

点击翻译按钮获取中文摘要

The major health issue developing in Australia is vascular and cardiovascular disease resulting from obesity and diabetes. Whilst prevention strategies based on lifestyle changes are preferable, treating cardiovascular risk factors with the latest drugs has been shown to produce significant benefits but there is a large remaining component of disease. New therapies are required and these will most likely target blood vessels directly. We are working on the basic cause of atherosclerosis with the aim of finding a mechanism and developing a drug to prevent the process - we have recently identified such a target and it is the subject of this research grant proposal. A group of very large molecules which have recently received increasing attention are the proteoglycans, combined protein-sugar molecules which are heavily coated with negatively charged groups. It has recently been published in the prestigious journal, Nature, that the binding of lipids in the blood to the wall of the blood vessel is the main cause of atherosclerosis. Proteoglycans are the molecules which cause the lipids to be stuck in blood vessels. Specifically, the length of the sugar (GAG) chains on the proteoglycan determines the binding of the lipids. We have now discovered a pathway and have one drug candidate which prevents the elongation of the GAG chains on proteoglycans. The exciting possibility is use of this agent with existing agents, for example, to use a statin drug to lower blood cholesterol and a new GAG elongation inhibitor to prevent the cholesterol sticking in the wall. The outcome will be the proof of the potential of a target for the direct therapy of atherosclerosis and a clear pathway for the development of a drug to be used in people susceptibility to atherosclerosis which is particularly people with diabetes.