Development of transgenic mice to determine the role of intelectins as effectors of gastrointestinal nematode expulsion

开发转基因小鼠以确定intelectin作为胃肠道线虫排出效应器的作用

基本信息

  • 批准号:
    BB/E008593/1
  • 负责人:
  • 金额:
    $ 5.43万
  • 依托单位:
  • 依托单位国家:
    英国
  • 项目类别:
    Research Grant
  • 财政年份:
    2007
  • 资助国家:
    英国
  • 起止时间:
    2007 至 无数据
  • 项目状态:
    已结题

项目摘要

Parasitic nematode worms that infest the gastrointestinal tract are an important human health concern in developing countries. Nematodes are a major problem for sheep and cattle farming in the UK, and world-wide, as they are increasingly resistant to anti-parasitic drugs. An alternative approach to drug-induced parasite control is to boost the natural immune reaction to parasites. Parasitism and allergy induce the same type of immune response, which has been studied extensively in rodents. The cells and signals involved are well known, but the way that these change the environment of the parasite and cause it to be expelled is less clear. Our recent work shows that the immune response to intestinal parasites results in levels of a protein, intelectin-2, which is produced by gut epithelial cells in greater amounts than any other protein in the vicinity of the parasite. In contrast, the protein intelectin-1 is present both before and after infection. We wish to test the hypothesis that intelectins, and particularly intelectin-2, contribute significantly to the immune expulsion of gut nematodes, while, at the same time, being aware of and testing alternative hypotheses on the function of this abundant protein. The project will aim to answer the following questions: 1. Does the increase in intelectin protein at the site of worm infestation influence the rate at which the parasite is expelled? 2. How does intelectin interact with other substances, such as mucus, in a way that could enhance rejection of parasites? 3. Do intelectins have anti-bacterial properties? We will use genetic engineering to create three new mouse lines in which to investigate the role of intelectins. Firstly, we will create a mutant of the 'C57BL/6' mouse strain, which naturally lacks the intelectin-2 gene, and make the mutant express the intelectin-2 protein. Furthermore, we will make 'knockout' mice on the 129 strain, which normally express intelectin-1 and intelectin-2, and make one line which is no longer able to make intelectin-2, and a second line that is unable to make either intelectin. By infecting these mice with worms and studying the rate of expulsion of the worms from the intestine of the mouse, we will be able to determine whether the ability to make intelectin proteins affects parasite rejection. We will also examine the properties of purified intelectins to see how they might relate to possible parasite rejection mechanisms. For example, does intelectin bind to the parasite or to bacteria? Does intelectin bind to mucus to make it thicker and help expel the parasite by engulfing it? At the end of the project, we will be in a position to say whether or not intelectins contribute significantly to parasite expulsion, and will know more of their properties. If intelectin does indeed help to expel parasites, then understanding how it works will help in the future design of vaccines to boost its parasite expelling effect. In terms of allergy, if intelectin causes mucus thickening, then it may similarly contribute to the life-threatening mucus plugging of the airways in acute asthma, and will therefore become an important new drug target.
在发展中国家,胃肠道寄生蠕虫是一个重要的人类健康问题。线虫是英国和世界范围内绵羊和牛养殖的主要问题,因为它们对抗寄生虫药物的耐药性越来越强。药物诱导的寄生虫控制的另一种方法是增强对寄生虫的天然免疫反应。寄生虫和变态反应诱导相同类型的免疫应答,这在啮齿动物中已被广泛研究。所涉及的细胞和信号是众所周知的,但这些改变寄生虫环境并导致其被驱逐的方式尚不清楚。我们最近的工作表明,对肠道寄生虫的免疫反应导致肠道上皮细胞产生的蛋白质intelectin-2的水平高于寄生虫附近的任何其他蛋白质。相反,蛋白质intelectin-1在感染之前和之后都存在。我们希望测试的假设,intelectin,特别是intelectin-2,有助于显着的肠道线虫的免疫驱逐,同时,在同一时间,正在意识到和测试替代假设的功能,这种丰富的蛋白质。该项目旨在回答以下问题:1。蠕虫感染部位的intelectin蛋白的增加是否会影响寄生虫的排出速度?2. intelectin如何与其他物质(如粘液)相互作用,从而增强对寄生虫的排斥?3. intelectins具有抗菌特性吗?我们将使用基因工程来创建三个新的小鼠品系,以研究intelectins的作用。首先,我们将从天然缺失intelectin-2基因的“C57 BL/6”小鼠品系中构建突变体,并使该突变体表达intelectin-2蛋白。此外,我们将在正常表达intelectin-1和intelectin-2的129品系上制造“敲除”小鼠,并制造一个不再能够制造intelectin-2的品系,以及第二个不能制造intelectin的品系。通过用蠕虫感染这些小鼠,并研究蠕虫从小鼠肠道排出的速度,我们将能够确定制造intelectin蛋白的能力是否影响寄生虫排斥。我们还将研究纯化的intelectin的特性,看看它们如何与可能的寄生虫排斥机制有关。例如,intelectin是与寄生虫结合还是与细菌结合?是否intelectin绑定粘液,使其更厚,并帮助驱逐寄生虫吞噬它?在项目结束时,我们将能够说是否intelectins有助于显着的寄生虫驱逐,并将知道更多的属性。如果intelectin确实有助于驱逐寄生虫,那么了解它的工作原理将有助于未来疫苗的设计,以提高其驱逐寄生虫的效果。在过敏方面,如果intelectin导致粘液增厚,那么它可能同样有助于急性哮喘中危及生命的气道粘液堵塞,因此将成为重要的新药靶点。

项目成果

期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Sheep intelectin-2 co-purifies with the mucin Muc5ac from gastric mucus.
绵羊 intelectin-2 与胃粘液中的粘蛋白 Muc5ac 共同纯化。
  • DOI:
    10.1016/j.rvsc.2011.03.004
  • 发表时间:
    2011
  • 期刊:
  • 影响因子:
    2.4
  • 作者:
    Pemberton AD
  • 通讯作者:
    Pemberton AD
The interaction of large bowel microflora with the colonic mucus barrier.
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Jeff Pearson其他文献

Measurement of stainer bath and slide contamination in batch h&e stainers
  • DOI:
    10.1016/s0031-3025(16)32627-7
  • 发表时间:
    2012-01-01
  • 期刊:
  • 影响因子:
  • 作者:
    John B. Carpenter;Angie Cahill;Jeff Pearson
  • 通讯作者:
    Jeff Pearson

Jeff Pearson的其他文献

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{{ truncateString('Jeff Pearson', 18)}}的其他基金

Physiologically relevant modelling of the aerodigestive tract as a delivery and screening platform for drugs and bioactives
呼吸消化道的生理相关模型作为药物和生物活性物质的输送和筛选平台
  • 批准号:
    BB/R019657/1
  • 财政年份:
    2018
  • 资助金额:
    $ 5.43万
  • 项目类别:
    Research Grant
An integrated upper GI model of digestion and absorption - the commercial 'Holy Grail'
消化和吸收的综合上消化道模型 - 商业“圣杯”
  • 批准号:
    BB/N012666/1
  • 财政年份:
    2016
  • 资助金额:
    $ 5.43万
  • 项目类别:
    Research Grant
A physiologically relevant in vitro model gut system
生理相关的体外模型肠道系统
  • 批准号:
    BB/M005631/1
  • 财政年份:
    2014
  • 资助金额:
    $ 5.43万
  • 项目类别:
    Research Grant
Designing the most effective vehicle to deliver alginate to effectively reduce fat digestion and absorption
设计最有效的海藻酸盐输送载体,有效减少脂肪消化吸收
  • 批准号:
    BB/K020307/1
  • 财政年份:
    2013
  • 资助金额:
    $ 5.43万
  • 项目类别:
    Research Grant
Bioactive Alginates and Obesity
生物活性藻酸盐与肥胖
  • 批准号:
    BB/G00563X/1
  • 财政年份:
    2008
  • 资助金额:
    $ 5.43万
  • 项目类别:
    Research Grant

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