Regulation of hydrogen peroxide-signalling by redox-sensitive peroxiredoxin and thioredoxin proteins

这项研究将研究单细胞真菌（酵母）如何使用抗氧化剂来分解和解毒过氧化氢，以感知过氧化氢水平的变化并调节细胞对这些变化的反应。过氧化氢是在空气中产生的活细胞作为一个不必要的副产品的新陈代谢。未经检查，过氧化氢会破坏细胞的DNA，蛋白质和脂质成分。这种类型的损害涉及许多疾病的发生和发展，包括心脏病、糖尿病和癌症，也涉及衰老过程。因为它是如此有毒，过氧化氢也是由植物和免疫细胞产生的，以杀死入侵的病原真菌和细菌。为了限制过氧化氢等化学物质的损害，细胞已经开发出了分解这些化学物质的保护性抗氧化剂。当细胞在环境中遇到过氧化氢时，它会被感知并传递信号，导致产生更多的抗氧化剂。我们之前的研究令人惊讶地发现，除了解毒过氧化氢之外，某些酵母还需要一个丰富的保守抗氧化剂家族，即过氧化物酶，通过开启这些抗氧化剂防御来感知和响应过氧化氢。随后，我们发现另一种抗氧化剂硫氧还蛋白也在感知和发出过氧化氢环境增加的信号中起着至关重要的作用。因此，该项目将建立在这个强大的已发表和试点数据平台上，以了解硫氧还蛋白和过氧化物氧还蛋白如何共同协调酵母裂殖酵母对过氧化氢的反应。该项目的成果将大大扩展我们对真菌如何检测和响应过氧化氢的理解。鉴于过氧化氢在消除入侵的病原微生物方面的重要性，我们预测，增加对抗氧化剂在细胞中如何发挥作用的理解可能会发现真菌感染的新治疗策略。虽然过氧化氢是非常有毒的，但最近发现植物和动物产生过氧化氢作为刺激细胞分裂，移动或变得专业化的信号。因此，这些研究也可以深入了解抗氧化剂如何影响这些信号传导过程。

This research will examine how a single cell fungus (yeast) uses antioxidants, that breakdown and detoxify hydrogen peroxide, to sense changes in the levels of hydrogen peroxide and regulate the response of cells to these changes. Hydrogen peroxide is produced in air-living cells as an unwanted byproduct of metabolism. Unchecked, hydrogen peroxide damages DNA, protein and lipid components of cells. This type of damage is involved in the initiation and progression of many diseases including heart disease, diabetes and cancer and also in the ageing process. Because it is so toxic hydrogen peroxide is also produced by plants and immune cells to kill invading pathogenic fungi and bacteria. To limit damage by chemicals such as hydrogen peroxide, cells have developed protective antioxidants which breakdown these chemicals. When cells encounter hydrogen peroxide in the environment this is sensed and signals are relayed that lead to the production of more antioxidants. Our previous research made the surprising discovery that, in addition to detoxifying hydrogen peroxide, one family of abundant, conserved antioxidants, the peroxiredoxins, is required by certain yeast to sense and respond to hydrogen peroxide by switching on these antioxidant defences. Subsequently, we have found that another antioxidant, thioredoxin, also plays a vital role in sensing and signalling environmental increases in hydrogen peroxide. Thus, this project will build on this strong platform of published and pilot data to understand how thioredoxin and peroxiredoxin together coordinate the response of the yeast Schizosaccharomyces pombe to hydrogen peroxide. The outcomes of this project will significantly extend our understanding of how fungi detect and respond to hydrogen peroxide. Given the importance of hydrogen peroxide in eliminating invading pathogenic microbes, we predict that an increased understanding of how antioxidants function in cells could uncover new therapeutic strategies for fungal infections. Although hydrogen peroxide is very toxic it has recently been discovered that plants and animals produce hydrogen peroxide as a signal to stimulate cells to divide, to move or to become specialised. Thus, these studies may also provide insight into how antioxidants affect these signalling processes.