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Can studying the mechanism of action of the parasitic worm-derived immunomodulator ES-62, inform on how to slow ageing and improve healthspan?

研究寄生虫源性免疫调节剂 ES-62 的作用机制能否为如何延缓衰老和改善健康提供信息？

基本信息

批准号：
BB/M029727/1
负责人：
Margaret Harnett
金额：
$ 51.24万
依托单位：
University of Glasgow
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2016
资助国家：
英国
起止时间：
2016 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FM029727%2F1
关键词：
studying mechanism action parasitic worm

项目摘要

The introduction of vaccines and drugs to control disease, in combination with greater access to food and improved sanitation, means that people are now living much longer. Currently this increase is staggering, equating to an extra 2.5 years of life per decade. However, improved life expectancy itself amounts to a huge new problem, in that it is not being accompanied by a similar increase in health and wellbeing. This reflects both that like a mechanical machine such as a car engine, the ageing process is naturally associated with a loss of function of its systems due to "wear and tear", but also that improved wealth has resulted in a modern Western life-style, incorporating a high fat diet (HFD) that contributes to age-associated ailments such as type-2 diabetes (T2D), stroke and heart disease. This impact of increased lifespan presenting with associated ill-health has enormous socio-economic implications due to its increasingly global scale, arguing for a need to better understand the process of ageing in the context of health.Approximately one quarter of the world's population is infected with parasitic worms. Of interest, several recent reports indicate that such infections offer protection against development of conditions such as obesity, cardiovascular disease and T2D in mouse models and that similar protection may also be seen in humans. We have been studying one individual parasitic worm component - ES-62, isolated from the secretory products of the filarial nematode, Acanthocheilonema viteae, and consistent with these studies, ES-62 is highly effective in reducing the cardiovascular disease that arises in a highly susceptible strain of mouse, particularly in response to a high fat diet. Moreover, we have some preliminary data showing that ES-62 may offer some protection against development of the obesity that is associated with development of T2D. Our studies to date with ES-62 also show it to be effective in inhibiting the development of disease in mouse models of allergy, rheumatoid arthritis and systemic lupus erythematosus. What all of these diseases have in common with cardiovascular disease and T2D is the increasing realization that they are associated with unwanted inflammation. This immediately offers an explanation for ES-62's protective effects, as the parasitic worm-derived molecule possesses a range of anti-inflammatory properties. Furthermore, as ageing is also now being considered as a biological problem in the setting of chronic low-grade inflammation, this raises the possibility of investigating the effect of ES-62 on the ageing process and late-life health and well being (healthspan). Thus, we specifically plan to determine whether ES-62 can slow ageing and improve healthspan using a paradigm where mice will be fed on a high fat diet +/- ES-62. We will use this model to assess the effect of ES-62 treatment on ageing in the context of promotion of gene signatures and signalling pathways known to be associated with ageing/inflammation versus those associated with longevity and healthspan. In addition to enabling us to establish whether ES-62's anti-inflammatory properties are impacting on the ageing process at the molecular level as predicted, this strategy might allow us to validate novel biomarkers for ageing and even potential sites of therapeutic intervention. With respect to the latter, we have produced synthetic drug-like small molecule analogues (SMAs) of ES-62 during our work on the allergy and autoimmunity models, with a view to using these as a starting point in novel drug development for these conditions. Thus, although the current application is designed to increase understanding of the biology of ageing rather than drug development, we will conduct a small trial with one of these SMAs towards the final year of the project with a view to submitting future grant applications for impact funding for their development as potential therapies.

控制疾病的疫苗和药物的使用，加上获得食物的机会增加和卫生条件的改善，意味着人们现在的寿命要长得多。目前这一增长是惊人的，相当于每十年增加2.5年的寿命。然而，预期寿命的提高本身就构成了一个巨大的新问题，因为它并没有伴随着健康和福祉的类似提高。这既反映了像汽车发动机这样的机械机器一样，衰老过程自然与“磨损”导致的系统功能丧失有关，也反映了财富的增加导致了现代西方生活方式，包括高脂肪饮食（HFD），这导致了与年龄相关的疾病，如2型糖尿病（T2D）、中风和心脏病。寿命延长与相关的健康状况不佳的影响由于其日益扩大的全球规模而具有巨大的社会经济影响，因此有必要更好地了解健康背景下的老龄化过程。大约四分之一的世界人口感染了寄生虫。有趣的是，最近的几份报告表明，在小鼠模型中，这种感染对肥胖、心血管疾病和T2D等疾病的发展提供了保护，并且在人类中也可能看到类似的保护。我们一直在研究一种单独的寄生虫成分——ES-62，从丝状线虫Acanthocheilonema viteae的分泌产物中分离出来，与这些研究一致，ES-62在减少一种高度易感的小鼠品系中出现的心血管疾病方面非常有效，特别是对高脂肪饮食的反应。此外，我们有一些初步数据显示ES-62可能对与T2D发展相关的肥胖发展提供一定的保护。迄今为止，我们对ES-62的研究也表明，它可以有效地抑制过敏、类风湿性关节炎和系统性红斑狼疮小鼠模型的疾病发展。所有这些疾病与心血管疾病和T2D的共同之处在于，人们越来越意识到它们与不必要的炎症有关。这立即为ES-62的保护作用提供了解释，因为寄生蠕虫衍生的分子具有一系列抗炎特性。此外，由于衰老现在也被认为是慢性低度炎症背景下的一个生物学问题，这增加了调查ES-62对衰老过程和晚年健康和福祉（healthspan）的影响的可能性。因此，我们特别计划确定ES-62是否可以延缓衰老和改善健康寿命，使用小鼠喂食高脂肪饮食+/- ES-62的范例。我们将使用该模型来评估ES-62治疗在促进已知与衰老/炎症相关的基因特征和信号通路与与长寿和健康相关的基因特征和信号通路的背景下对衰老的影响。除了使我们能够确定ES-62的抗炎特性是否如预测的那样在分子水平上影响衰老过程外，该策略还可以让我们验证新的衰老生物标志物，甚至是潜在的治疗干预位点。对于后者，我们已经在过敏和自身免疫模型的研究中生产了ES-62的合成药物样小分子类似物（sma），以期将其作为针对这些疾病的新药开发的起点。因此，虽然目前的申请旨在增加对衰老生物学的理解，而不是药物开发，但我们将在项目的最后一年对其中一个sma进行小型试验，以期提交未来的拨款申请，以获得影响基金，以开发潜在的治疗方法。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Protection Against Arthritis by the Parasitic Worm Product ES-62, and Its Drug-Like Small Molecule Analogues, Is Associated With Inhibition of Osteoclastogenesis.

DOI：
10.3389/fimmu.2018.01016
发表时间：
2018
期刊：
Frontiers in immunology
影响因子：
7.3
作者：
Doonan J;Lumb FE;Pineda MA;Tarafdar A;Crowe J;Khan AM;Suckling CJ;Harnett MM;Harnett W
通讯作者：
Harnett W

Protection against lung pathology during obesity-accelerated ageing in mice by the parasitic worm product ES-62.