TRANSCRIPTIONAL AND FUNCTIONAL CONSEQUENCES OF STAT3 ACTIVATION IN THE HEART

心脏中 STAT3 激活的转录和功能后果

• 批准号: nhmrc : 353592
• 负责人: A/Pr Marie Bogoyevitch
• 金额: $ 27.59万
• 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 2009-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/transcriptional-functional-consequences-activation-heart/96990
• 关键词: TRANSCRIPTIONAL; FUNCTIONAL; CONSEQUENCES; STAT3; ACTIVATION

Recent statistics show that the disease known commonly as heart failure accounts for about 3000 deaths each year in Australia. Worldwide, a staggering 10 million people are thought to currently suffer from heart failure, with this number continuing to rise despite decreasing numbers of people suffering from other forms of heart and blood vessel disease. What causes a healthy heart to fail remains unclear, although in some circumstances failure is known to be initiated by genetic factors, viral factors, alcoholism, high blood pressure, or when the heart is damaged in a heart attack. We are interested in the molecular mechanisms that underlie the progression of the normal heart to failure. In 2003 we reported on altered signalling pathways in the failing human heart, and noted the increased phosphorylation of a spliceform of the transcription factor STAT3 in patients with heart failure. In this project, we will evaluate a larger group of heart failure patients for changes in phosphorylation of their STAT3 proteins. We will also increase the expression of an activated form of the STAT3 proteins in rat heart cells, and check whether there are accompanying changes in gene expression profiles that indicate a potential role in heart failure, or whether these cells are now predisposed to die. This will be extended with the use of transgenic animals (mice) engineered to overexpress activated STAT3 proteins. Again, we will focus on gene expression profiles. We will also evaluate whether the hearts of these animals are more likely to fail, either as the animals age, or when external stresses are experienced. With this information, we will be able to state whether STAT3 is a contributor to heart failure, and therefore whether it is an attractive target for future therapies aimed at reducing the morbidity and mortality of heart failure worldwide.

最近的统计数据显示，这种通常被称为心力衰竭的疾病每年在澳大利亚造成约3000人死亡。在世界范围内，目前有1000万人患有心力衰竭，尽管患有其他形式的心脏和血管疾病的人数减少，但这一数字仍在继续上升。是什么原因导致健康的心脏衰竭仍然不清楚，尽管在某些情况下，已知衰竭是由遗传因素，病毒因素，酗酒，高血压或心脏病发作时心脏受损引发的。我们感兴趣的是正常心脏发展到衰竭的分子机制。在2003年，我们报道了在衰竭的人类心脏中改变的信号通路，并注意到在心力衰竭患者中转录因子STAT 3的剪接形式的磷酸化增加。在这个项目中，我们将评估一个更大的组心力衰竭患者的STAT3蛋白磷酸化的变化。我们还将增加大鼠心脏细胞中活化形式的STAT3蛋白的表达，并检查基因表达谱是否伴随着表明心力衰竭潜在作用的变化，或者这些细胞现在是否倾向于死亡。这将通过使用被工程化以过表达活化的STAT3蛋白的转基因动物（小鼠）来扩展。我们将再次关注基因表达谱。我们还将评估这些动物的心脏是否更容易衰竭，无论是随着动物年龄的增长，还是当经历外部压力时。有了这些信息，我们将能够说明STAT3是否是心力衰竭的一个促成因素，因此它是否是未来旨在降低全球心力衰竭发病率和死亡率的治疗的一个有吸引力的目标。