INNATE IMMUNE RESPONSES TO MALARIA PARASITE

对疟疾寄生虫的先天免疫反应

基本信息

  • 批准号:
    7845034
  • 负责人:
  • 金额:
    $ 35.43万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    1998
  • 资助国家:
    美国
  • 起止时间:
    1998-01-15 至 2012-05-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Pro-inflammatory mediators produced in response to Plasmodium falciparum infection contribute to severe malaria. However, very little is known about the mechanism by which these immune responses are elicited and are regulated. The glycosylphosphatidylinositols (GPIs) have been proposed as the major parasite factors that contribute to malaria pathogenesis. Previously, we showed that GPI-induced activation of macrophages is mediated mainly by TLR2 via the activation of the MyD88-dependent MAPK and NF-KB pathways, which differentially contribute to the production of pro-inflammatory mediators. Since GPIs are membrane bound and are not released during schizont burst, which produces peak levels of pro-inflammatory responses, it is important to study the physiologically relevant parasite components that are the targets of the immune system with regard to the host receptor specificity and receptor-dependent modulation of innate immune responses. Further, little or no information is available on the receptor specificity in the recognition of parasites by dendritic cells (DCs), which play crucial role in the initiation and modulation of innate immunity. Extending the work done during the previous grant period, we propose the following Specific Aims: (1) To study the mechanism of ERK-dependent dysregulation of GPI-induced IL-6 and IL-12 production and to investigate the requirement of TLR1 or TLR6 for recognition of GPIs.(2) To investigate the receptor specificity in the pro-inflammatory responses to parasite schizont-released components in macrophages and DCs, and activation of T cell responses by DCs. (3) To determine in vivo whether the receptor specificity of P. berghei mirrors the ligand-receptor specificity observed for the major TLR ligands of P. falciparum. (4) To study the malaria parasite-induced tolerance with regard to switching from pro- to anti-inflammatory responses by macrophages and DCs, and the modulation of T cell responses by DCs. The overall goal is to gain in-depth understanding of the mechanisms of cell signaling and regulation of innate immune responses to malaria parasite. The long-term objectives of this project are to understand in detail the mechanisms of innate immune responses to P. falciparum infection and to use this knowledge for therapeutic benefit. Malaria is a major public health crisis around the world, affecting ~40% of the population and killing 2- 3 million people annually. Currently, malaria is spreading rapidly due to drug resistance. A large number of people from non-malaria regions (military and business personnel, diplomats and visitors) are also at increased risk and are particularly more vulnerable to severe or even fatal forms of the disease because of their non-immune status. Therefore, novel drugs/therapeutic and/or vaccine are needed urgently. The knowledge gained by the studies proposed in this application should prove valuable in combating malaria.
描述(由申请人提供):响应恶性疟原虫感染而产生的促炎性介质会导致严重的疟疾。但是,对于这些免疫反应被引起并受到调节的机制知之甚少。已经提出,已提出糖基磷脂酰肌醇(GPI)是导致疟疾发病机理的主要寄生虫因子。以前,我们表明GPI诱导的巨噬细胞的激活主要是由TLR2通过激活MyD88依赖性MAPK和NF-KB途径介导的,这有助于产生促炎性介体的产生。由于GPI是膜的结合,并且在Schizont爆发过程中未释放,这会产生峰值水平 促炎的反应,重要的是研究与宿主受体特异性和依赖于先天免疫反应的受体依赖性调节有关的生理相关寄生虫成分。此外,在树突状细胞(DC)识别寄生虫中,几乎没有或根本没有有关受体特异性的信息,这些寄生虫在先天免疫的启动和调节中起着至关重要的作用。扩展在上一个赠款期间所做的工作,我们提出以下具体目的:(1)研究ERK依赖性失调的GPI诱导的IL-6和IL-12产生的机制,并研究TLR1或TLR6的需求,以识别GPIS对GPIS的识别。 DC和DC激活T细胞反应。 (3)在体内确定P. berghei的受体特异性是否反映了针对恶性疟原虫的主要TLR配体观察到的配体受体特异性。 (4)研究疟原虫诱导的耐受性在从巨噬细胞和DC从促炎反应转换为抗炎反应方面,以及DC对T细胞反应的调节。总体目标是深入了解细胞信号的机制以及对疟原虫寄生虫的先天免疫反应的调节。该项目的长期目标是详细了解对恶性疟原虫感染的先天免疫反应的机制,并将这些知识用于治疗益处。 疟疾是世界各地的主要公共卫生危机,影响了约40%的人口,杀死2-- 每年300万人。目前,由于耐药性,疟疾正在迅速扩散。来自非马拉里亚地区(军事和商业人员,外交官和访客)的大量人也处于风险增加,由于其非免疫地位,尤其容易受到严重甚至致命的疾病形式。因此,紧急需要新颖的药物/治疗和/或疫苗。本应用程序提出的研究获得的知识应证明对抗疟疾有价值。

项目成果

期刊论文数量(0)
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专利数量(0)

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CHANNE D GOWDA其他文献

CHANNE D GOWDA的其他文献

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{{ truncateString('CHANNE D GOWDA', 18)}}的其他基金

Therapeutic targeting of malarial placental cytoadherence
疟疾胎盘细胞粘附的治疗靶向
  • 批准号:
    9303868
  • 财政年份:
    2015
  • 资助金额:
    $ 35.43万
  • 项目类别:
Therapeutic targeting of malarial placental cytoadherence
疟疾胎盘细胞粘附的治疗靶向
  • 批准号:
    9097541
  • 财政年份:
    2015
  • 资助金额:
    $ 35.43万
  • 项目类别:
Malaria Research Training in South India
印度南部的疟疾研究培训
  • 批准号:
    7933399
  • 财政年份:
    2010
  • 资助金额:
    $ 35.43万
  • 项目类别:
INNATE IMMUNE RESPONSES TO MALARIA PARASITE
对疟疾寄生虫的先天免疫反应
  • 批准号:
    8099841
  • 财政年份:
    2010
  • 资助金额:
    $ 35.43万
  • 项目类别:
Malaria Research Training in South India
印度南部的疟疾研究培训
  • 批准号:
    8666095
  • 财政年份:
    2010
  • 资助金额:
    $ 35.43万
  • 项目类别:
Malaria Research Training in South India
印度南部的疟疾研究培训
  • 批准号:
    8109997
  • 财政年份:
    2010
  • 资助金额:
    $ 35.43万
  • 项目类别:
Malaria Research Training in South India
印度南部的疟疾研究培训
  • 批准号:
    8475399
  • 财政年份:
    2010
  • 资助金额:
    $ 35.43万
  • 项目类别:
CYTOADHERENCE IN MATERNAL MALARIA
母体疟疾中的细胞粘附
  • 批准号:
    2841559
  • 财政年份:
    1999
  • 资助金额:
    $ 35.43万
  • 项目类别:
CYTOADHERENCE IN MATERNAL MALARIA
母体疟疾中的细胞粘附
  • 批准号:
    6554926
  • 财政年份:
    1999
  • 资助金额:
    $ 35.43万
  • 项目类别:
CYTOADHERENCE IN MATERNAL MALARIA
母体疟疾中的细胞粘附
  • 批准号:
    7005706
  • 财政年份:
    1999
  • 资助金额:
    $ 35.43万
  • 项目类别:

相似海外基金

INNATE IMMUNE RESPONSES TO MALARIA PARASITE
对疟疾寄生虫的先天免疫反应
  • 批准号:
    8099841
  • 财政年份:
    2010
  • 资助金额:
    $ 35.43万
  • 项目类别:
INNATE IMMUNE RESPONSES TO MALARIA PARASITE
对疟疾寄生虫的先天免疫反应
  • 批准号:
    7433323
  • 财政年份:
    1998
  • 资助金额:
    $ 35.43万
  • 项目类别:
INNATE IMMUNE RESPONSES TO MALARIA PARASITE
对疟疾寄生虫的先天免疫反应
  • 批准号:
    7617839
  • 财政年份:
    1998
  • 资助金额:
    $ 35.43万
  • 项目类别:
INNATE IMMUNE RESPONSES TO MALARIA PARASITE
对疟疾寄生虫的先天免疫反应
  • 批准号:
    7313057
  • 财政年份:
    1998
  • 资助金额:
    $ 35.43万
  • 项目类别:
INNATE IMMUNE RESPONSES TO MALARIA PARASITE
对疟疾寄生虫的先天免疫反应
  • 批准号:
    8069834
  • 财政年份:
    1998
  • 资助金额:
    $ 35.43万
  • 项目类别:
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