Pon3, a natural antioxidant protein: its role in development and disease.

Pon3，一种天然抗氧化蛋白：其在发育和疾病中的作用。

• 批准号: MR/K013300/1
• 负责人: Steve Charnock-Jones
• 金额: $ 53万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FK013300%2F1
• 关键词: Pon3; natural; antioxidant; protein; its

Oxygen plays a critical role in maintaining life but because it is highly reactive, cells have multiple defences to protect themselves from oxidative stress and damage. The detrimental effects of oxidative stress are increased with age and oxidative stress is a well-recognised feature of several common major conditions including diabetes, metabolic syndrome, neurodegenerative diseases and age-related macular degeneration. At birth the fetus is exposed to a rapid and substantial increase in oxygen as it begins to breathe and many defence systems are up-regulated at this time. We therefore searched for previously unrecognised or novel endogenous antioxidants which are up-regulated in late gestation in the fetus. Such molecules may be useful therapeutically in the pre-term infant but may also be important components of the adult anti-oxidant defence system. They may also be perturbed in some of the pathologies characterised by oxidative stress.We carried out this search and identified paraoxonase 3 (Pon3). This protein is strongly induced in the lung and gut prior to birth in rats, mice, sheep and humans and at least in the sheep, this is controlled by glucocorticoid hormones. We conclude that this may be a systemic preparative process for birth.The paraoxonase family consists of 3 closely related enzymes which break down a wide range of molecules from several different biologically important families. These include hormone-like molecules, lipid peroxides, the oxidation products of arachidonic acid and estrogen esters. Thus, the Pons have the potential to modulate the signalling pathways mediated by such molecules. These enzymes also effectively break down molecules that bacteria use to regulate their growth in situations where many bacteria are present (as may be the case in the intestine for example). They also break down toxic pesticides.In blood, PON1 is associated with lipid-containing particles and it can reduce the harmful inflammatory action of oxidized lipid. Artificially increasing PON3 levels in mice inhibited atherosclerotic lesion formation and body fat and Pons in general are antioxidants and anti-inflammatory. In humans mutations in the PON1 gene alter the risk of heart attack and stroke. Thus, in addition to their presumed role as potent circulating antioxidants, these enzymes have anti-atherogenic and anti-inflammatory properties; are capable of metabolising derivatives of important regulatory hormones; can degrade pesticides and have the potential to alter host/microbe interaction. As such, they are implicated in diverse and important biological processes and have attracted considerable attention. Despite this, the physiological function of this family of well-conserved enzymes remains unclear.To understand the normal role of Pon3 we have used a genetically engineered mice in which the Pon3 gene has been knocked-out. When we bred heterozygous mice together there were significantly fewer Pon3-/- animals than expected (25% expected but only 9% found). The mutant mice die early in pregnancy so we conclude that Pon3 has an essential and non-redundant biological role in early embryonic development.We predict that loss of or a reduction in Pon3 will lead to increased oxidative stress hence embryonic lethality or reduced embryonic growth. We will investigate this using detailed histological, biochemical and molecular methods in normal and Pon3 knockout mice. Furthermore, this reduction of Pon3 may exacerbate oxidative stress and disease sensitivity in adult life. We will engineer conditional knockout mice and study how loss of Pon3 effects mice as they age and are fed a high fat diet.These studies will determine whether Pon3 plays a role in protecting mice from the detrimental effects of age and a poor diet. The biochemical studies will identify pathways that are likely to be similar in humans allowing us in future studies to determine whether Pon3 may be important in human disease.

氧气在维持生命方面起着至关重要的作用，但由于它具有高度反应性，细胞具有多种防御机制来保护自己免受氧化应激和损伤。氧化应激的有害影响随着年龄的增长而增加，氧化应激是几种常见主要疾病的公认特征，包括糖尿病，代谢综合征，神经退行性疾病和年龄相关性黄斑变性。在出生时，胎儿暴露于氧气的快速和大量增加，因为它开始呼吸，许多防御系统在这个时候上调。因此，我们寻找以前未认识到的或新的内源性抗氧化剂，在妊娠后期的胎儿上调。这样的分子在治疗上可用于早产儿，但也可以是成人抗氧化防御系统的重要组分。他们也可能会受到干扰，在一些病理特征的氧化stress.We进行了这项搜索，并确定对氧磷酶3（Pon 3）。这种蛋白质在出生前在大鼠、小鼠、绵羊和人类的肺和肠道中强烈诱导，至少在绵羊中，这是由糖皮质激素控制的。对氧磷酶家族由3种密切相关的酶组成，它们分解来自几个不同生物学重要家族的广泛分子。这些物质包括类花生四烯酸分子、脂质过氧化物、花生四烯酸的氧化产物和雌激素酯。因此，脑桥具有调节这些分子介导的信号传导途径的潜力。这些酶还能有效地分解细菌用来调节其生长的分子，在许多细菌存在的情况下（例如在肠道中）。在血液中，PON 1与含脂质颗粒相关，它可以减少氧化脂质的有害炎症作用。小鼠体内PON 3水平的显著增加抑制了动脉粥样硬化病变的形成和体脂，而脑桥通常是抗氧化剂和抗炎剂。在人类中，PON 1基因的突变改变了心脏病发作和中风的风险。因此，除了它们作为有效循环抗氧化剂的假定作用外，这些酶具有抗动脉粥样硬化和抗炎特性;能够代谢重要调节激素的衍生物;可以降解农药并具有改变宿主/微生物相互作用的潜力。因此，它们涉及各种重要的生物过程，并引起了相当大的关注。尽管如此，这个保守酶家族的生理功能仍然不清楚。为了了解Pon 3的正常作用，我们使用了一个基因工程小鼠，其中Pon 3基因已被敲除。当我们将杂合子小鼠一起繁殖时，Pon 3-/-动物比预期的要少得多（预期为25%，但仅发现9%）。突变小鼠在妊娠早期死亡，因此我们得出结论，Pon 3在早期胚胎发育中具有重要的和非冗余的生物学作用。我们预测Pon 3的缺失或减少将导致氧化应激增加，从而导致胚胎死亡或减少胚胎生长。我们将在正常和Pon 3基因敲除小鼠中使用详细的组织学、生物化学和分子方法对此进行研究。此外，Pon 3的这种减少可能会加剧成年生活中的氧化应激和疾病敏感性。我们将设计条件性基因敲除小鼠，并研究Pon 3的缺失如何影响衰老和高脂肪饮食的小鼠。这些研究将确定Pon 3是否在保护小鼠免受年龄和不良饮食的不利影响方面发挥作用。生化研究将确定在人类中可能相似的途径，使我们能够在未来的研究中确定Pon 3是否可能在人类疾病中起重要作用。