Bioengineering of Cyclotides with Angiogenic Properties

动脉粥样硬化是一种逐渐堵塞的动脉，在澳大利亚、欧洲、美国和日本是导致死亡的主要原因。冠心病（冠心病；冠状动脉堵塞），虽然在世界上大多数地区继发于动脉粥样硬化，但仅在欧洲每年就造成近200万人死亡。在澳大利亚，冠心病是唯一的主要死因。该项目旨在开发先导分子，用于开发能够刺激循环缓慢或迟缓组织的血运重建（即打开阻塞的血管以改善血液流动）的治疗方法。这种疗法将改善动脉粥样硬化和冠心病的治疗。多肽是一种小蛋白质，通常不够稳定，不能用作药物。在这个项目中，我们计划设计基于一个异常稳定的蛋白质家族的蛋白质分子，被称为环核苷酸。我们将化学合成已被改变的环核苷酸类似物，以纳入能够诱导治疗性血管生成的不太稳定的小肽的活性。鉴于冠心病的普遍性，开发有效的治疗方法可能对该病的经济成本产生深远的影响，在美国，这一成本每年达到1332亿美元。该项目涉及分子生物科学研究所的研究人员与血管生物学研究中心的研究人员之间的合作，前者具有药物设计和蛋白质化学方面的专业知识，后者具有血管生物学和血管工程方面的专业知识。这两个研究所都是昆士兰大学的一部分。

Atherosclerosis, a gradual clogging of the arteries, is the single leading cause of death in Australia, Europe, the USA and Japan. Coronary heart disease (CHD; clogging of the coronary arteries), while secondary to atherosclerosis in most of the world, accounts for nearly 2 million deaths per year in Europe alone. In Australia CHD is the single leading cause of death. This project is aimed at developing lead molecules for the development of therapeutics capable of stimulating revascularization (that is, opening up blocked vessels to improve blood flow) of tissues with slow or retarded circulation. Such therapeutics would improve the treatment of atherosclerosis and CHD. Peptides, small proteins, are generally not stable enough to be used as drugs. In this project we plan to engineer protein molecules based on an unusually stable family of proteins, known as the cyclotides. We will chemically synthesise analogues of cyclotides that have been altered to incorporate the activities of less stable small peptides that are able to induce therapeutic angiogenesis. Given the prevalence of CHD, the development of effective therapeutics could have a profound impact on the economic cost of the disease, which in the USA amounts to US$133.2 billion per year. This project involves collaboration between researchers from the Institute for Molecular Bioscience, who have expertise in drug design and protein chemistry, and researchers from the Centre for Research in Vascular Biology, who have expertise in vascular biology and vessel engineering. Both of these institutes are part of the University of Queensland.