Role of advanced glycation end products and their receptors in diabetes accelerated atherosclerosis

糖尿病在西方世界正在增加，随着这种增加，并发症的负担也在增加。其中之一是动脉粥样硬化，它会导致心脏病发作、中风和坏疽。在这项研究中，我们考虑了糖与称为晚期糖化的蛋白质结合的生化反应的作用，以及这些晚期糖化蛋白质（AGEs）如何与特定受体相互作用以促进动脉粥样硬化。我们将使用过表达受体RAGE或缺失该受体基因的新型动物模型。我们将研究这些动物在患糖尿病时是否能预防血管疾病，并将揭示相关的机制。此外，我们将研究新的药物，以阻止血管损伤的糖尿病小鼠模型容易动脉粥样硬化。这些干预措施之一将涉及给予受体的游离形式，其将捕获循环中的AGEs并防止它们与血管壁中的AGEs结合。这种治疗原则已在动物身上证明可以预防糖尿病的血管疾病。我们还将向这些易患动脉粥样硬化的小鼠和转基因小鼠喂食糖连接蛋白（AGEs），以观察这些蛋白质如何直接影响血管壁，即使不存在糖尿病。这些研究将最终导致更好的治疗方法，以预防，减缓或逆转糖尿病的血管损伤。

Diabetes is on the increase in the Western world and with this increase comes the burden of increased complications. One of these is atherosclerosis which leads to heart attacks, strokes and gangrene. In this grant we consider the role of a biochemical reaction where sugar attaches to proteins called advanced glycation and how these advaced glycated proteins (AGEs) interact with specific receptors to promote atherosclerosis. We will use novel animal models overexpressing the receptor RAGE or with deletion of the gene for this receptor. We will investigate if these animals are protected against blood vessel disease when made diabetic and will unravel the mechanisms involved. Furthermore we will investigate novel drugs to block vessel damage in a model of diabetic mice prone to atherosclerosis. One of these interventions will involve giving a free form of the receptor RAGE which will trap the circulating AGEs and prevent them from binding to RAGE in the blood vessel wall. This therpeutic principle has been shown in animals to prevent blood vessel disease in diabetes. We will also feed the sugar-attached proteins (AGEs) to these mice prone to atherosclerosis and to the genetically modified mice to see how these proteins directly influence the vessel wall even if diabetes is not present. These studies will ultimately lead to better treatments to prevent, slow down or reverse blood vessel damage in diabetes.