Suppression of NADPH oxidase-derived Oxidative Stress by Anti-sense Probes and HDL in Human Vascular Endothelium

反义探针和 HDL 对人血管内皮细胞中 NADPH 氧化酶衍生的氧化应激的抑制

• 批准号: nhmrc : 350482
• 负责人: Prof Fan Jiang
• 金额: $ 30.36万
• 依托单位: The University of Melbourne
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2005
• 资助国家: 澳大利亚
• 起止时间: 2005-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/suppression-nadph-oxidase-vascular-endothelium/78422
• 关键词: Suppression; NADPH; oxidase; derived; Oxidative

In Australia, coronary heart disease (CHD) causing heart attacks remains the largest cause of death, claiming a staggering 28,000 lives a year. Oxidative stress, resulting from increased production of oxygen free radicals in arteries, is an important cause of CHD, heart attacks and strokes. We seek to understand how such oxyradicals are produced in the key cells that form the lining of all arteries, known as the vascular endothelium. By using novel DNA-type molecules (known as anti-sense) developed in our laboratory, which block a particular gene causing oxidative stress, we will determine whether this gene is responsible for the formation of oxyradicals in human and mouse cells grown in culture. In addition, we will explore whether this gene is turned on by factors known to be involved in CHD. Finally, we will also investigate whether the good cholesterol known as HDL can act to prevent oxidative stress in human cells, as we discovered it appears to do in living arteries in vivo. If we find it has the same protective effect in endothelium, we will determine how it does this, and which component proteins of the HDL particle are important. This might suggest new treatments to prevent acute events leading to heart attack and stroke, and possibly new applications where damage appears to result from acute oxidative stress, such as in the brain soon after a stroke has occurred. We also have a plan to develop antisense drugs that will target the important gene specifically in the affected endothelium. In addition, we have other specific new drugs that will block this system in arteries. Simultaneously we will be testing the role of this gene in mouse and rabbit models of artery disease, for both our types of drugs might provide valuable new therapeutic agents to target the underlying cause of CHD and not just its symptoms as current drugs do.

在澳大利亚，导致心脏病发作的冠心病（CHD）仍然是最大的死亡原因，每年夺去28，000人的生命。氧化应激是由动脉中氧自由基的产生增加引起的，是冠心病、心脏病发作和中风的重要原因。我们试图了解这些氧自由基是如何在形成所有动脉内膜的关键细胞中产生的，这些细胞被称为血管内皮。通过使用我们实验室开发的新型DNA型分子（称为反义），它阻断了引起氧化应激的特定基因，我们将确定该基因是否负责培养中生长的人类和小鼠细胞中氧自由基的形成。此外，我们还将探讨该基因是否被已知参与CHD的因素所开启。最后，我们还将研究被称为HDL的好胆固醇是否可以防止人体细胞中的氧化应激，就像我们发现它在体内活动脉中所做的那样。如果我们发现它在内皮细胞中具有相同的保护作用，我们将确定它是如何做到这一点的，以及HDL颗粒的哪些组分蛋白是重要的。这可能会提出新的治疗方法来预防导致心脏病发作和中风的急性事件，以及可能的新应用，其中损伤似乎是由急性氧化应激引起的，例如中风发生后不久的大脑。我们还计划开发反义药物，专门针对受影响的内皮细胞中的重要基因。此外，我们还有其他特定的新药，可以阻断动脉中的这一系统。同时，我们将在小鼠和家兔动脉疾病模型中测试该基因的作用，因为我们的两种药物都可能提供有价值的新治疗药物，以靶向冠心病的根本原因，而不仅仅是目前药物的症状。