Collectins and Innate Defense against Inhaled Pathogens
Collectins and Innate Defense against Inhaled Pathogens
批准号:
7924146
负责人:
BARBARA A SEATON
金额:
$193.83万
依托单位国家:
美国
项目类别:
财政年份:
2009
资助国家:
美国
项目状态:
已结题
起止时间:
2009-09-01 至 2012-08-31
中文摘要
该计划项目的中心主题是了解宿主的固有防御机制,
吸入的病原体通过两种肺表面活性蛋白A和D(SP-A、SP-D)聚集。这
理解不仅在流行的呼吸道感染的背景下很重要,
与严重的全球生物威胁有关的是,出现了抗药性生物;进化和
更致命的呼吸道病毒的迅速传播;以及吸入的病原体可能用于
生物恐怖主义有效的肺部宿主防御需要早期识别微生物。以下
当微生物沉积到呼吸道中时,病原体有一个关键的机会窗口,
清除;延迟反应有利于感染。肺聚集素在先天性心脏病中起着重要作用,
防御许多革兰氏阴性和阳性细菌及其内毒素,分枝杆菌,致病性
真菌和专性细胞内病原体,包括甲型流感病毒(IAV)和其他潜在致死病毒。
肺聚集素的先天防御特性取决于它们的快速识别,并且在某些情况下,
例,基于高度保守的微生物模式识别的吸入微生物中和
表面组分,如lAV上的N-连接高甘露糖聚糖和革兰氏阴性脂多糖
(内毒素)。其他研究表明,缺乏肺聚集蛋白动物表现出显著增加
对微生物挑战的敏感性。重组截短型SP-A和SP-D在小鼠体内的研究
过敏和感染的模型提供了这些蛋白质的雾化形式传递的可能性,
通过吸入可能在控制呼吸道感染、炎症和过敏方面具有治疗潜力,
人类在这个程序项目中,一个高度协作和重点突出的项目组使用互补的
方法,包括X射线晶体学,诱变,光谱学,体外和体内分析,
动物模型,专门针对胶原聚集蛋白的先天反应,以及调节胶原聚集蛋白的蛋白质,如KGF,
他们的活动,以lAV和革兰氏阴性细菌都获得机制的理解,并协助设计
具有增加的抗微生物活性的潜在的基于胶原凝集素的治疗剂。
.
英文摘要
The central theme of the Program Project is to understand the innate host defense mechanisms against
inhaled pathogens by the two pulmonary collectins, surfactant proteins A and D (SP-A, SP-D). This
understanding is important not only in the context of prevalent respiratory infections but also those
associated with serious global biothreats ¿ the emergence of antibiotic-resistant organisms; evolution and
rapid spread of more lethal respiratory viruses; and potential use of inhaled pathogens in acts of
bioterrorism. Effective pulmonary host defense requires early recognition of microorganisms. Following
deposition of an organism into the respiratory tract, there is a critical window of opportunity for pathogen
clearance; delayed response favors infection. The pulmonary collectins play a front-line role in the innate
defense against many gram-negative and positive bacteria and their endotoxins, mycobacteria, pathogenic
fungi, and obligate intracellular pathogens including influenza A (lAV) and other potentially lethal viruses.
The innate defense properties of pulmonary collectins depend upon their rapid recognition and, in some
cases, neutralization of inhaled microorganisms based on pattern recognition of highly-conserved microbial
surface components such as N-linked high-mannose glycans on lAV and gram-negative lipolysaccharide
(endotoxin). Other studies show that animals deficient in lung collectins show significantly increased
susceptibility to microbiological challenges. Studies of recombinant truncated SP-A and SP-D in murine
models of allergy and infection have offered the possibility that aerosolized forms of these proteins delivered
by inhalation may have therapeutic potential in controlling respiratory infection, inflammation, and allergy in
humans. In this program project, a highly collaborative and focused group of projects using complementary
approaches, including x-ray crystallography, mutagenesis, spectroscopy, in vitro and in vivo analyses using
animal models, aim specifically at innate responses of collectins, and proteins such as KGF that modulate
their activity, to lAV and gram-negative bacteria both to gain mechanistic understanding and assist design of
potential collectin-based therapeutics with increased antimicrobial activities.
.
期刊论文(5)
专著(0)
科研奖励(0)
会议论文
Crystallographic complexes of surfactant protein A and carbohydrates reveal ligand-induced conformational change.
表面活性剂蛋白 A 和碳水化合物的晶体复合物揭示了配体诱导的构象变化。
DOI:
10.1074/jbc.m110.175265
发表时间:
2011
期刊:
The Journal of biological chemistry
影响因子:
--
作者:
[Shang,Feifei, Rynkiewicz,MichaelJ, McCormack,FrancisX, Wu,Huixing, Cafarella,TanyaM, Head,JamesF, Seaton,BarbaraA]
通讯作者:
Seaton,BarbaraA
Differential Ligand Binding Specificities of the Pulmonary Collectins Are Determined by the Conformational Freedom of a Surface Loop.
肺集合素的差异配体结合特异性由表面环的构象自由度决定。
DOI:
10.1021/acs.biochem.6b01313
发表时间:
2017
期刊:
Biochemistry
影响因子:
2.9
作者:
[Rynkiewicz,MichaelJ, Wu,Huixing, Cafarella,TanyaR, Nikolaidis,NikolaosM, Head,JamesF, Seaton,BarbaraA, McCormack,FrancisX]
通讯作者:
McCormack,FrancisX
DOI:
10.1016/j.bbamem.2009.11.024
发表时间:
2010-04
期刊:
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES
影响因子:
3.4
作者:
[Mendelsohn, Richard, Mao, Guangru, Flach, Carol R.]
通讯作者:
Flach, Carol R.
Collectins and Innate Defense against Inhaled Pathogens
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批准号:7695978
-
项目类别:
-
资助金额:$203.58万
-
财政年份:2009
-
负责人:BARBARA A SEATON
-
依托单位:
Collectins and Innate Defense against Inhaled Pathogens
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批准号:7932334
-
项目类别:
-
资助金额:$94.56万
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财政年份:2009
-
负责人:BARBARA A SEATON
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依托单位:
PHOSPHOLIPID HEAD GROUP RECOGNITION IN MEMBRANE BINDING PROTEIN ANNEXIN V
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批准号:6345252
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项目类别:
-
资助金额:$0.38万
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财政年份:2000
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负责人:BARBARA A SEATON
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依托单位:
PHOSPHOLIPID HEAD GROUP RECOGNITION IN MEMBRANE BINDING PROTEIN ANNEXIN V
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批准号:6478976
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项目类别:
-
资助金额:$5.36万
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财政年份:2000
-
负责人:BARBARA A SEATON
-
依托单位:
PHOSPHOLIPID HEAD GROUP RECOGNITION IN MEMBRANE BINDING PROTEIN ANNEXIN V
-
批准号:6206447
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项目类别:
-
资助金额:$0.38万
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财政年份:1999
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负责人:BARBARA A SEATON
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依托单位:
CA BRIDGING MECHANISM & PHOSPHOLIPID HEAD GROUP RECOGNITION IN ANNEXIN V
-
批准号:6123287
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项目类别:
-
资助金额:$0.0万
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财政年份:1998
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负责人:BARBARA A SEATON
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依托单位:
ANNEXIN CRYSTAL STRUCTURES AND MEMBRANE INTERACTIONS
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批准号:2182572
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项目类别:
-
资助金额:$22.45万
-
财政年份:1990
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负责人:BARBARA A SEATON
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依托单位:
ANNEXIN CRYSTAL STRUCTURES AND MEMBRANE INTERACTIONS
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批准号:6476516
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项目类别:
-
资助金额:$26.17万
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财政年份:1990
-
负责人:BARBARA A SEATON
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依托单位:
ANNEXIN CRYSTAL STRUCTURE AND PHOSPHOLIPID INTERACTION
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批准号:3468143
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项目类别:
-
资助金额:$10.31万
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财政年份:1990
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负责人:BARBARA A SEATON
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依托单位:
ANNEXIN CRYSTAL STRUCTURES AND MEMBRANE INTERACTIONS
-
批准号:2444753
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项目类别:
-
资助金额:$23.13万
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财政年份:1990
-
负责人:BARBARA A SEATON
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依托单位:
ANNEXIN CRYSTAL STRUCTURES AND MEMBRANE INTERACTIONS
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批准号:2904412
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项目类别:
-
资助金额:$27.2万
-
财政年份:1990
-
负责人:BARBARA A SEATON
-
依托单位:
ANNEXIN CRYSTAL STRUCTURE AND PHOSPHOLIPID INTERACTION
-
批准号:3468145
-
项目类别:
-
资助金额:$11.9万
-
财政年份:1990
-
负责人:BARBARA A SEATON
-
依托单位:
ANNEXIN CRYSTAL STRUCTURES AND MEMBRANE INTERACTIONS
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批准号:6625079
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项目类别:
-
资助金额:$26.94万
-
财政年份:1990
-
负责人:BARBARA A SEATON
-
依托单位:
ANNEXIN CRYSTAL STRUCTURES AND MEMBRANE INTERACTIONS
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批准号:6085175
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项目类别:
-
资助金额:$11.53万
-
财政年份:1990
-
负责人:BARBARA A SEATON
-
依托单位:
ANNEXIN CRYSTAL STRUCTURE AND PHOSPHOLIPID INTERACTION
-
批准号:2182570
-
项目类别:
-
资助金额:$12.76万
-
财政年份:1990
-
负责人:BARBARA A SEATON
-
依托单位:
ANNEXIN CRYSTAL STRUCTURES AND MEMBRANE INTERACTIONS
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批准号:2734659
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项目类别:
-
资助金额:$24.04万
-
财政年份:1990
-
负责人:BARBARA A SEATON
-
依托单位:
ANNEXIN CRYSTAL STRUCTURE AND PHOSPHOLIPID INTERACTION
-
批准号:3468144
-
项目类别:
-
资助金额:$11.23万
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财政年份:1990
-
负责人:BARBARA A SEATON
-
依托单位:
ANNEXIN CRYSTAL STRUCTURES AND MEMBRANE INTERACTIONS
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批准号:6329723
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项目类别:
-
资助金额:$25.42万
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财政年份:1990
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负责人:BARBARA A SEATON
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依托单位:
ANNEXIN CRYSTAL STRUCTURES AND MEMBRANE INTERACTIONS
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批准号:2182571
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项目类别:
-
资助金额:$23.82万
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财政年份:1990
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负责人:BARBARA A SEATON
-
依托单位:
ANNEXIN CRYSTAL STRUCTURE AND PHOSPHOLIPID INTERACTION
-
批准号:3468146
-
项目类别:
-
资助金额:$11.82万
-
财政年份:1990
-
负责人:BARBARA A SEATON
-
依托单位:
国内基金
海外基金
Innate-likeB细胞受损介导凋亡细胞的清除障碍在系统性红斑狼疮发病中的作用及机制研究
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批准号:81860295
-
项目类别:地区科学基金项目
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资助金额:35.0万元
-
批准年份:2018
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负责人:张伟
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依托单位: