Sphingolipid biosynthesis in the parasitic apicomplexan protozoa: divergent enzymes in key host:pathogen interactions

寄生顶复门原生动物中的鞘脂生物合成:关键宿主中的不同酶:病原体相互作用

基本信息

  • 批准号:
    BB/M024156/1
  • 负责人:
  • 金额:
    $ 46.43万
  • 依托单位:
  • 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

项目摘要

IntroductionThe apicomplexans are a large group of related, single-celled microscopic organisms that cause a range of diseases (including malaria) in both humans and economically important domestic animals. One of these, Toxoplasma gondii, can infect most species of warm-blooded animal causing a disease known as toxoplasmosis. In recent times toxoplasmosis has come to prominence as a serious disease in patients whose defences (immune response) against infectious microbes have been damaged, such as those suffering from Acquired ImmunoDeficiency Syndrome (AIDS) and those undergoing anti-cancer chemotherapy. Furthermore, during normal pregnancy infection of the unborn child with Toxoplasma is a major cause of miscarriage and congenital defects in humans. Similarly, Toxoplasma causes the spontaneous abortion of unborn lambs, leading to annual multi-million pound losses to UK sheep farmers.The ProblemHumans and other animals usually become infected with Toxoplasma following ingestion of faeces from the infected cats, or via contaminated food. Subsequently, the parasites can invade almost any of the cells that make up the body. However, in most cases this infection does not cause serious disease, instead Toxoplasma is controlled by the immune response of the human or animal and retreats into cysts in muscle tissues or the brain. These cysts can remain throughout the host's life without causing any physical problems, although some studies have linked the cysts to behavioral changes and mental illness in humans. However, a damaged (in an AIDS or cancer patient) or undeveloped (in an unborn human or animal) immune response is unable to control the parasite in this way and serious disease occurs, commonly leading to severe brain damage. Unfortunately, the few available drugs to treat the diseases caused by Toxoplasma and other apicomplexan parasites show severe problems with effectiveness and major side-effects, meaning that there is an urgent need to discover new therapies for both human and animal health.The BackgroundWithin the human or animal cell Toxoplasma manufactures many molecules it needs for growth, however it is also able to scavenge various materials that it uses for its own purposes. Sphingolipids are essential components of the Toxoplasma plasma membrane (the fatty barrier that separates the inside of the parasite cell from the external environment). Our previous work has shown that although the parasite can scavenge sphingolipid from the host animal cell, this process is not essential for growth and the spread of infection. This indicated that the machinery that Toxoplasma possesses to synthesize the essential sphingolipids is likely to be crucial for its survival and ability to cause disease. The AimsWe have identified key enzyme components of this machinery and this research proposal aims to exploit these findings by: [i] Demonstrating that Toxoplasma sphingolipid synthesis is essential for the parasite; and [ii] Characterizing the identified enzymes, the components of the sphingolipid machinery. The data generated will facilitate future work to exploit the Toxoplasma (and other apicomplexan parasites') sphingolipid synthesis machinery as a target for new, much needed, drugs.
前言顶端复合体是一大群相互关联的单细胞微生物,在人类和经济上重要的家畜中都能引起一系列疾病(包括疟疾)。其中之一,弓形虫,可以感染大多数种类的温血动物,导致一种被称为弓形虫病的疾病。近年来,弓形虫病作为一种严重的疾病在对感染微生物的防御(免疫反应)受到破坏的患者中日益突出,例如患有获得性免疫缺陷综合症(AIDS)的患者和接受抗癌化疗的患者。此外,在正常怀孕期间,胎儿感染弓形虫是人类流产和先天缺陷的主要原因。同样,弓形虫会导致未出生的羊羔自然流产,导致英国牧羊人每年损失数百万英镑。问题人类和其他动物通常在摄入受感染猫的粪便或通过受污染的食物后感染弓形虫。随后,寄生虫可以入侵几乎所有组成人体的细胞。然而,在大多数情况下,这种感染不会导致严重的疾病,相反,弓形虫由人或动物的免疫反应控制,并退缩到肌肉组织或大脑中的包囊中。这些包囊可以在宿主的一生中保留下来,而不会造成任何身体问题,尽管一些研究已经将这些包囊与人类的行为变化和精神疾病联系起来。然而,受损的(艾滋病或癌症患者)或未发育的(未出生的人或动物)免疫反应无法以这种方式控制寄生虫,从而发生严重疾病,通常导致严重的脑损伤。不幸的是,现有的治疗弓形虫和其他顶端复合体寄生虫引起的疾病的药物在有效性和主要副作用方面存在严重问题,这意味着迫切需要寻找新的治疗方法来治疗人类和动物的健康。背景在人或动物细胞内,弓形虫制造许多生长所需的分子,但它也能够清除用于自身目的的各种物质。鞘磷脂是弓形体膜(将寄生虫细胞内部与外部环境隔开的脂肪屏障)的重要组成部分。我们之前的工作表明,虽然寄生虫可以从宿主动物细胞中清除鞘脂,但这一过程对生长和感染的传播并不是必不可少的。这表明弓形虫合成必需鞘脂的机制可能对其生存和致病能力至关重要。目的我们已经确定了这种机制的关键酶成分,这项研究计划旨在通过以下方式利用这些发现:[i]证明弓形虫鞘脂的合成对寄生虫是必不可少的;以及[ii]表征所识别的酶,即鞘脂机制的组件。产生的数据将有助于未来利用弓形虫(和其他顶端复合体寄生虫)鞘脂合成机制作为新的、急需的药物靶标的工作。

项目成果

期刊论文数量(10)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
The antifungal Aureobasidin A and an analogue are active against the protozoan parasite Toxoplasma gondii but do not inhibit sphingolipid biosynthesis - Corrigendum.
  • DOI:
    10.1017/s0031182017000877
  • 发表时间:
    2018-03
  • 期刊:
  • 影响因子:
    2.4
  • 作者:
    Alqaisi AQI;Mbekeani AJ;Llorens MB;Elhammer AP;Denny PW
  • 通讯作者:
    Denny PW
Toxoplasma ceramide synthases: a curious case of gene duplication, divergence and key functionality
  • DOI:
    10.1101/2022.01.05.475179
  • 发表时间:
    2022-01
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Zisis Koutsogiannis;John G. M. Mina;C. Albus;M. Kol;J. Holthuis;E. Pohl;P. Denny
  • 通讯作者:
    Zisis Koutsogiannis;John G. M. Mina;C. Albus;M. Kol;J. Holthuis;E. Pohl;P. Denny
Repurposing as a strategy for the discovery of new anti-leishmanials: the-state-of-the-art.
  • DOI:
    10.1017/s0031182017000993
  • 发表时间:
    2018-03
  • 期刊:
  • 影响因子:
    2.4
  • 作者:
    Charlton RL;Rossi-Bergmann B;Denny PW;Steel PG
  • 通讯作者:
    Steel PG
The antifungal Aureobasidin A and an analogue are active against the protozoan parasite Toxoplasma gondii but do not inhibit sphingolipid biosynthesis.
  • DOI:
    10.1017/s0031182017000506
  • 发表时间:
    2018-03
  • 期刊:
  • 影响因子:
    2.4
  • 作者:
    Alqaisi AQI;Mbekeani AJ;Llorens MB;Elhammer AP;Denny PW
  • 通讯作者:
    Denny PW
Complex Interplay between Sphingolipid and Sterol Metabolism Revealed by Perturbations to the Leishmania Metabolome Caused by Miltefosine.
  • DOI:
    10.1128/aac.02095-17
  • 发表时间:
    2018-05
  • 期刊:
  • 影响因子:
    4.9
  • 作者:
    Armitage EG;Alqaisi AQI;Godzien J;Peña I;Mbekeani AJ;Alonso-Herranz V;López-Gonzálvez Á;Martín J;Gabarro R;Denny PW;Barrett MP;Barbas C
  • 通讯作者:
    Barbas C
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Paul Denny其他文献

Empowering Education with LLMs - The Next-Gen Interface and Content Generation
通过法学硕士赋能教育——下一代界面和内容生成
First Things First: Providing Metacognitive Scaffolding for Interpreting Problem Prompts
首先要事:为解释问题提示提供元认知支架
  • DOI:
  • 发表时间:
    2019
  • 期刊:
  • 影响因子:
    0
  • 作者:
    J. Prather;Raymond Pettit;Brett A. Becker;Paul Denny;Dastyni Loksa;Alani L. Peters;Zachary Albrecht;Krista Masci
  • 通讯作者:
    Krista Masci
Decoding Logic Errors: A Comparative Study on Bug Detection by Students and Large Language Models
解码逻辑错误:学生和大型语言模型错误检测的比较研究
Instructor Perceptions of AI Code Generation Tools - A Multi-Institutional Interview Study
教师对人工智能代码生成工具的看法——多机构访谈研究
Exploring the Difficulty of Faded Parsons Problems for Programming Education
探讨帕森斯褪色问题对编程教育的难度

Paul Denny的其他文献

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{{ truncateString('Paul Denny', 18)}}的其他基金

MRC IAA 2021 Durham University
MRC IAA 2021 杜伦大学
  • 批准号:
    MR/X502947/1
  • 财政年份:
    2022
  • 资助金额:
    $ 46.43万
  • 项目类别:
    Research Grant
Mining for new drug and vaccine targets in Toxoplasma gondii sphingolipid biosynthesis - applications in animal and human health
弓形虫鞘脂生物合成中新药和疫苗靶点的挖掘——在动物和人类健康中的应用
  • 批准号:
    BB/T003987/1
  • 财政年份:
    2019
  • 资助金额:
    $ 46.43万
  • 项目类别:
    Research Grant
A Global Network for Neglected Tropical Diseases
被忽视的热带病全球网络
  • 批准号:
    MR/P027989/1
  • 财政年份:
    2017
  • 资助金额:
    $ 46.43万
  • 项目类别:
    Research Grant
Toxoplasma: Sphingolipids in host-parasite interactions syntheses versus scavenging
弓形虫:宿主-寄生虫相互作用中的鞘脂合成与清除
  • 批准号:
    BB/D52396X/1
  • 财政年份:
    2006
  • 资助金额:
    $ 46.43万
  • 项目类别:
    Research Grant

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