Mechanism of Activation of Innate Immunity by ISS-DNA
ISS-DNA 激活先天免疫的机制
基本信息
- 批准号:6744001
- 负责人:
- 金额:$ 27.48万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2002
- 资助国家:美国
- 起止时间:2002-05-15 至 2006-04-30
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
DESCRIPTION (provided by applicant): Innate immunity enables an organism to
respond rapidly to invading microorganisms. To do this, innate immune system
uses a variety of receptors or intracellular proteins that can recognize a
microbial pathogen by the motifs pathogen-associated molecular patterns
(PAMPs). Pathogen-associated motifs include mannans in the yeast cell wall,
formylated peptides and various bacterial cell-wall components such as
lipopolysaccharide (LPS), lipopeptides, peptidoglycans and teichoic acids.
Bacterial DNA is also a potent inducer of innate immunity.
Bacterial DNA contains increased frequency of CpG dinucleotide motifs in
particular sequence contexts (PuPuCpGPyPy), which are greatly reduced in
frequency in the mammalian genome, and where it occurs, the cytosine commonly
is methylated. DNA containing unmethylated CpG motifs is immunostimulatory and
able to activate cellular component of innate immunity, including macrophages
and dendritic cells (DC) as well as B cells. Thus, DNA containing unmethylated
CpG motif in sequences of PuPuCpGPyPy is also called ISS-DNA. Activation of
immune cells by ISS-DNA appears to require uptake into the cells by receptor-
or pinocytosis-mediated endocytosis and endosome acidification, suggesting that
the recognition structure is either endosome-associated or cytoplasmic. Recent
studies suggested that Toll-like receptor (TLR) 9 and adapter protein MyD88 are
required for ISS-DNA to induce immune cells to produce interlukin-12, and for
activation of NF-kB by ISS-ODN. The studies from our group suggested that
catalytic subunit of DNA-dependent protein kinase (DNAPKcs) and IkB kinase
(IKK) are required for the activation of innate immunity by ISS-DNA. ISS-DNA
activates DNA-PKcs, which in turn activates IKK, leading to NF-kB activation.
Null mutations in either the DNA-PKcs- or IKKb gene were found to selectively
impair the ability of mice or their macrophages, to respond to ISS-DNA with
inducible cytokine gene expression.
TLR9 is on cell membrane while DNA-PKcs is in cytoplasm and nucleus. The
connection between TLR9 and DNA-PKcs is not apparent. To further understand the
molecular mechanisms of activation of innate immunity by ISS-DNA, we will
investigate the relationship between TLR9-signaling pathway and DNA-PK by using
biochemical and genetic means. Moreover, we will investigate if the regulatory
subunits of DNA-PK, Ku70 and Ku80, and their associated factors are required
for the innate response to ISS-DNA. Furthermore, we will identify new molecules
that are required for activation of innate immunity by ISS-DNA.
描述(由申请人提供):先天免疫使生物体能够
对入侵微生物的反应迅速。为此,先天免疫系统
使用各种可以识别的受体或细胞内蛋白
基序与病原体相关的分子模式微生物病原体
(小型小型)。病原体相关的基序包括酵母细胞壁中的曼纳斯
甲基化的肽和各种细菌细胞壁成分,例如
脂多糖(LPS),脂蛋白肽,肽糖和te菌酸。
细菌DNA也是先天免疫的有效诱导剂。
细菌DNA包含CPG二核苷酸基序的频率增加
特定序列上下文(pupucpgpypy),大大降低了
哺乳动物基因组的频率及其发生的地方,胞嘧啶通常
被甲基化。含有未甲基化CPG基序的DNA是免疫刺激的,并且
能够激活先天免疫的细胞成分,包括巨噬细胞
和树突状细胞(DC)以及B细胞。因此,含有未甲基化的DNA
pupucpgpypy序列中的CpG基序也称为ISS-DNA。激活
ISS-DNA的免疫细胞似乎需要受体吸收细胞
或生物细胞增多介导的内吞作用和内体酸化,表明
识别结构是内体相关或细胞质的。最近的
研究表明,Toll样受体(TLR)9和适配器蛋白MyD88是
ISS-DNA需要诱导免疫细胞产生Interlukin-12,而对于
ISS-ODN激活NF-KB。我们小组的研究表明
DNA依赖性蛋白激酶(DNAPKC)和IKB激酶的催化亚基
(IKK)通过ISS-DNA激活先天免疫需要。 ISS-DNA
激活DNA-PKC,从而激活IKK,导致NF-KB激活。
发现DNA-PKCS-或IKKB基因中的空突变有选择地
损害小鼠或其巨噬细胞的能力,用
诱导性细胞因子基因表达。
TLR9在细胞膜上,而DNA-PKC在细胞质和核中。这
TLR9和DNA-PKC之间的连接并不明显。进一步了解
通过ISS-DNA激活先天免疫的分子机制,我们将
通过使用TLR9信号途径与DNA-PK之间的关系
生化和遗传手段。此外,我们将调查监管是否
DNA-PK,KU70和KU80的亚基及其相关因素是需要的
对ISS-DNA的天生反应。此外,我们将确定新分子
通过ISS-DNA激活先天免疫所必需的。
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)
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Wen-Ming Chu其他文献
Wen-Ming Chu的其他文献
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{{ truncateString('Wen-Ming Chu', 18)}}的其他基金
Mechansim of activation of innate immunity by ISS-DNA
ISS-DNA激活先天免疫的机制
- 批准号:
7583102 - 财政年份:2009
- 资助金额:
$ 27.48万 - 项目类别:
Mechansim of activation of innate immunity by ISS-DNA
ISS-DNA激活先天免疫的机制
- 批准号:
7795913 - 财政年份:2009
- 资助金额:
$ 27.48万 - 项目类别:
Mechansim of activation of innate immunity by ISS-DNA
ISS-DNA激活先天免疫的机制
- 批准号:
8240074 - 财政年份:2009
- 资助金额:
$ 27.48万 - 项目类别:
Mechansim of activation of innate immunity by ISS-DNA
ISS-DNA激活先天免疫的机制
- 批准号:
8068827 - 财政年份:2009
- 资助金额:
$ 27.48万 - 项目类别:
Mechansim of activation of innate immunity by ISS-DNA
ISS-DNA激活先天免疫的机制
- 批准号:
8444603 - 财政年份:2009
- 资助金额:
$ 27.48万 - 项目类别:
Mechanism of Activation of Innate Immunity by ISS-DNA
ISS-DNA 激活先天免疫的机制
- 批准号:
6589209 - 财政年份:2002
- 资助金额:
$ 27.48万 - 项目类别:
Mechanism of Activation of Innate Immunity by ISS-DNA
ISS-DNA 激活先天免疫的机制
- 批准号:
6885363 - 财政年份:2002
- 资助金额:
$ 27.48万 - 项目类别:
Mechanism of Activation of Innate Immunity by ISS-DNA
ISS-DNA 激活先天免疫的机制
- 批准号:
6640821 - 财政年份:2002
- 资助金额:
$ 27.48万 - 项目类别:
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