A structured transcriptional switching network that coordinates antigenic variation by malaria parasites

协调疟原虫抗原变异的结构化转录转换网络

基本信息

  • 批准号:
    10319714
  • 负责人:
  • 金额:
    $ 70.33万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-09-22 至 2026-08-31
  • 项目状态:
    未结题

项目摘要

Project Summary/Abstract Plasmodium falciparum is the causative agent responsible for the most severe form of human malaria, a disease that kills more than 400,000 people a year, mostly young children in Africa. These protozoan parasites invade and ultimately destroy circulating red blood cells (RBCs) of their host, leading to severe anemia and the frequently lethal syndromes of cerebral malaria and pregnancy associated malaria. Over the course of an infection, small sub-populations of parasites arise that have an altered antigenic phenotype, thus avoiding the antibody response of the host. This process is referred to as antigenic variation and is responsible for the persistent nature of the disease as well as the waves of parasitemia frequently observed in P. falciparum infections. Antigenic variation of P. falciparum infected RBCs results from switches in expression between individual members of the multi-copy var gene family. Each var gene encodes a different form of a protein called PfEMP1. This protein is placed on the infected RBC surface and mediates adhesion to specific receptors found on the endothelial surfaces of the blood vessel walls of the infected individual. This adhesion is responsible for many of the disease manifestations of infection with P. falciparum, including both cerebral malaria and pregnancy associated malaria. Only a single var gene is expressed at a time by any given parasite, thus determining both the antigenic phenotype of the infected cells as well as their adhesive properties. Therefore var gene expression is at the heart of both antigenic variation and virulence of malaria infections. The long-term objectives of this project are to understand the molecular mechanisms that regulate var gene expression and antigenic variation by malaria parasites. Significant work in recent years has defined many molecular aspects that maintain a gene in the active or silent state, however the mechanisms governing switching between transcriptionally active genes remain entirely undefined. Moreover, given that an infection can include billions of individual parasites, how they seemingly coordinate switching events to limit activation to a single or small number of genes at a time is completely unexplored. In contrast, uncoordinated, random switching would rapidly exhaust the entire var repertoire. There is no evidence of communication between parasites, and there does not appear to be a strict switching order within the var gene family, therefore how this is accomplished remains completely mysterious. The specific aims of the project are designed to decipher the mechanistic basis of this phenomenon. Aim 1 investigates the role of an unusual, highly conserved var gene that appears to function as central organizing gene that coordinates switching events. Aim 2 will determine how parasites sense the presence of a placenta and alter var gene expression to take advantage of this unusual niche. This project will contribute to the ongoing effort to disrupt the process of antigenic variation and thereby shorten the length of an infection and reduce its severity.
项目总结/摘要 恶性疟原虫是导致最严重的人类疟疾的病原体, 这种疾病每年导致40多万人死亡,其中大多数是非洲的儿童。这些原生动物 寄生虫侵入并最终破坏其宿主的循环红细胞(RBC),导致严重的 贫血以及脑型疟疾和妊娠相关疟疾的频繁致死综合征。超过 在感染过程中,出现了小的寄生虫亚群,它们具有改变的抗原性, 表型,从而避免宿主的抗体应答。这一过程被称为抗原性 变异,并负责疾病的持续性以及寄生虫血症的波 常见于恶性疟原虫感染。恶性疟原虫感染红细胞的抗原变异结果 来自多拷贝var基因家族的个体成员之间的表达开关。每个var基因 编码一种不同形式的蛋白质PfEMP 1。这种蛋白质被放置在受感染的红细胞表面 并介导粘附于在血管壁的内皮表面上发现的特异性受体, 被感染的个体。这种粘连是造成许多感染的疾病表现的原因 与恶性疟原虫感染,包括脑型疟疾和妊娠相关疟疾。只有一个变量 基因在任何给定的寄生虫中同时表达,从而决定了寄生虫的抗原表型 感染的细胞以及它们的粘附特性。因此,var基因表达是两者的核心。 抗原变异和疟疾感染的毒力。该项目的长期目标是 了解调节var基因表达和抗原变异的分子机制, 疟原虫近年来的重要工作已经定义了许多维持一种生物学特性的分子方面。 基因处于活跃或沉默状态,然而,控制转录之间切换的机制 活性基因仍然完全不确定。此外,考虑到感染可能包括数十亿人, 寄生虫,他们似乎如何协调开关事件,以限制激活到一个单一的或少量的 基因是完全未知的。相比之下,不协调的随机切换将迅速 耗尽了所有的无功功率没有证据表明寄生虫之间有交流, 在var基因家族中似乎没有严格的转换顺序,因此这是如何 完成的事情仍然是完全神秘的。该项目的具体目标是破译 这一现象的机械基础。目的1研究一个不寻常的,高度保守的变异的作用 一个似乎起着协调转换事件的中央组织基因作用的基因。目标2将 确定寄生虫如何感知胎盘的存在并改变var基因表达以获取 这个不寻常的利基优势。这一项目将有助于目前正在进行的努力, 抗原变异,从而缩短感染的时间并降低其严重性。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Kirk W Deitsch其他文献

The mystery of persistent, asymptomatic emPlasmodium falciparum/em infections
  • DOI:
    10.1016/j.mib.2022.102231
  • 发表时间:
    2022-12-01
  • 期刊:
  • 影响因子:
    7.500
  • 作者:
    Xu Zhang;Kirk W Deitsch
  • 通讯作者:
    Kirk W Deitsch

Kirk W Deitsch的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Kirk W Deitsch', 18)}}的其他基金

2022 Biology of Host-Parasite Interactions GRC and GRS
2022年寄主与寄生虫相互作用的生物学GRC和GRS
  • 批准号:
    10461307
  • 财政年份:
    2022
  • 资助金额:
    $ 70.33万
  • 项目类别:
Mechanisms of environmental sensing and responses by malaria parasites
疟原虫的环境感知和响应机制
  • 批准号:
    10160766
  • 财政年份:
    2018
  • 资助金额:
    $ 70.33万
  • 项目类别:
Mechanisms of environmental sensing and responses by malaria parasites
疟原虫的环境感知和响应机制
  • 批准号:
    10409750
  • 财政年份:
    2018
  • 资助金额:
    $ 70.33万
  • 项目类别:
DNA repair and recombination within the var gene family of P. falciparum
恶性疟原虫 var 基因家族内的 DNA 修复和重组
  • 批准号:
    8896210
  • 财政年份:
    2012
  • 资助金额:
    $ 70.33万
  • 项目类别:
DNA repair and recombination within the var gene family of P. falciparum
恶性疟原虫 var 基因家族内的 DNA 修复和重组
  • 批准号:
    8438018
  • 财政年份:
    2012
  • 资助金额:
    $ 70.33万
  • 项目类别:
DNA repair and recombination within the var gene family of P. falciparum
恶性疟原虫 var 基因家族内的 DNA 修复和重组
  • 批准号:
    8549946
  • 财政年份:
    2012
  • 资助金额:
    $ 70.33万
  • 项目类别:
DNA repair and recombination within the var gene family of P. falciparum
恶性疟原虫 var 基因家族内的 DNA 修复和重组
  • 批准号:
    9120780
  • 财政年份:
    2012
  • 资助金额:
    $ 70.33万
  • 项目类别:
DNA repair and recombination within the var gene family of P. falciparum
恶性疟原虫 var 基因家族内的 DNA 修复和重组
  • 批准号:
    8898709
  • 财政年份:
    2012
  • 资助金额:
    $ 70.33万
  • 项目类别:
DNA repair and recombination within the var gene family of P. falciparum
恶性疟原虫 var 基因家族内的 DNA 修复和重组
  • 批准号:
    8712356
  • 财政年份:
    2012
  • 资助金额:
    $ 70.33万
  • 项目类别:
Var gene regulation and antigenic variation in malaria
疟疾中的 Var 基因调控和抗原变异
  • 批准号:
    7234045
  • 财政年份:
    2002
  • 资助金额:
    $ 70.33万
  • 项目类别:

相似海外基金

I-Corps: Translation Potential of Peptidic Ensembles as Novel Bio-adhesives
I-Corps:肽整体作为新型生物粘合剂的转化潜力
  • 批准号:
    2409620
  • 财政年份:
    2024
  • 资助金额:
    $ 70.33万
  • 项目类别:
    Standard Grant
Architectural design of active adhesives
活性粘合剂的结构设计
  • 批准号:
    2403716
  • 财政年份:
    2024
  • 资助金额:
    $ 70.33万
  • 项目类别:
    Standard Grant
Design of non-swellable adhesives for brain surgery using cyclodextrin inclusion polymer
使用环糊精包合物聚合物脑外科不可溶胀粘合剂的设计
  • 批准号:
    23H01718
  • 财政年份:
    2023
  • 资助金额:
    $ 70.33万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Meta-material adhesives for improved performance and functionalisation of bondlines
超材料粘合剂可提高粘合层的性能和功能化
  • 批准号:
    EP/W019450/1
  • 财政年份:
    2023
  • 资助金额:
    $ 70.33万
  • 项目类别:
    Fellowship
Light-propelled dental adhesives with enhanced bonding capability
具有增强粘合能力的光驱动牙科粘合剂
  • 批准号:
    10741660
  • 财政年份:
    2023
  • 资助金额:
    $ 70.33万
  • 项目类别:
DMREF: Accelerating the Design of Adhesives with Nanoscale Control of Thermomechanical Properties
DMREF:通过热机械性能的纳米级控制加速粘合剂的设计
  • 批准号:
    2323317
  • 财政年份:
    2023
  • 资助金额:
    $ 70.33万
  • 项目类别:
    Continuing Grant
Mag-Cure: A novel method for magnetically induced bonding and de-bonding of thermoset adhesives in the Automotive Industry
Mag-Cure:汽车行业中热固性粘合剂磁感应粘合和脱粘的新方法
  • 批准号:
    10062336
  • 财政年份:
    2023
  • 资助金额:
    $ 70.33万
  • 项目类别:
    Collaborative R&D
Biodegradable, Biocompatible Pressure Sensitive Adhesives
可生物降解、生物相容性压敏粘合剂
  • 批准号:
    10677869
  • 财政年份:
    2022
  • 资助金额:
    $ 70.33万
  • 项目类别:
Poly(glycerol carbonate) pressure sensitive adhesives for the in vivo closure of alveolar pleural fistulae
用于体内闭合肺泡胸膜瘘的聚(甘油碳酸酯)压敏粘合剂
  • 批准号:
    10746743
  • 财政年份:
    2022
  • 资助金额:
    $ 70.33万
  • 项目类别:
Enhanced bio-production of difficult to make peptide ingredients for specialty adhesives and personal care
增强用于特种粘合剂和个人护理品的难以制造的肽成分的生物生产
  • 批准号:
    10021363
  • 财政年份:
    2022
  • 资助金额:
    $ 70.33万
  • 项目类别:
    Investment Accelerator
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了