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

在澳大利亚发展的主要健康问题是肥胖和糖尿病引起的血管和心血管疾病。虽然以改变生活方式为基础的预防策略是可取的，但用最新的药物治疗心血管风险因素已显示出显著的益处，但仍有很大一部分疾病存在。需要新的治疗方法，这些方法很可能直接针对血管。我们正在研究动脉粥样硬化的基本原因，目的是找到一种机制并开发一种药物来预防这一过程——我们最近确定了这样一个目标，这是本研究资助提案的主题。最近受到越来越多关注的一组非常大的分子是蛋白质多糖，它是蛋白质-糖分子的结合体，被带负电荷的基团包裹着。最近发表在权威杂志《自然》上的一篇文章指出，血液中的脂质与血管壁的结合是动脉粥样硬化的主要原因。蛋白聚糖是导致脂质滞留在血管中的分子。具体来说，蛋白聚糖上的糖（GAG）链的长度决定了脂质的结合。我们现在已经发现了一种途径，并且有一种候选药物可以阻止GAG链在蛋白聚糖上的延伸。令人兴奋的可能性是将这种药物与现有的药物一起使用，例如，使用他汀类药物来降低血液胆固醇和使用新的GAG延长抑制剂来防止胆固醇粘在壁上。这一结果将证明动脉粥样硬化直接治疗靶点的潜力，并为开发一种用于动脉粥样硬化易感性人群（特别是糖尿病患者）的药物提供了明确的途径。

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.