Collectins and Innate Defense against Inhaled Pathogens

集合素和针对吸入病原体的先天防御

基本信息

  • 批准号:
    7932334
  • 负责人:
  • 金额:
    $ 94.56万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2009
  • 资助国家:
    美国
  • 起止时间:
    2009-09-30 至 2011-08-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): 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. PROJECT 1: Vibrational Spectroscopy: Collectin Interactions with Physiological Ligands (Mendelsohn, R) PROJECT 1 DESCRIPTION (provided by applicant): The long term objective of this project is to elucidate the molecular basis by which collectins in the lung provide the first challenge to airborne pathogens in host defense. The surfactant specific collectins SP-A and SP-D, through their interactions with lipopolysaccharides (LPS), are responsible in part for this activity. With the technological expertise in novel vibrational spectroscopic approaches developed in this lab, we propose two specific aims to characterize the interaction of both proteins with physiological LPS derivatives. With the expertise of the other investigators in the program project, we will have access to a large number of genetic variants of these proteins, permitting us to pinpoint the primary interaction sites in a variety of biologically relevant physical preparations. Two specific aims are proposed. First, since both collectins recognize carbohydrate and other polar ligand sites, we will determine those collectin structural factors important for binding to LPS and its variants in Langmuir films (i.e. monolayers) at the air/water interface using a unique vibrational spectroscopy experiment (Infrared Reflection Absorption Spectroscopy- IRRAS) that extracts molecular structural and orientational information from the monolayer constituents. These films mimic polar regions of bacterial Gram negative outer membrane monolayers. The integrating hypothesis for this Aim is that at the level of molecular structure, the interaction between collectins and LPS depends on particular elements of protein structure and emphasizes specific regions of the collectin-carbohydrate recognition domain. Raman micro crystallography complements IRRAS and provides very specific structural information about protein side chains involved in the initial recognition event. In the second Aim, we will complement studies of protein structural changes with IR experiments that track structural changes both in the acyl chains and in the polar regions of the LPS derivatives. We will monitor collectin/LPS interaction under conditions where Langmuir films are not the only reasonable experimental paradigm. Physical states of lipid and lipid/protein complexes from which structural information will be acquired include vesicles, monolayers, supported oriented multibilayers, and micelles.
项目描述(由申请人提供):本项目的中心主题是了解两种肺聚集素,表面活性剂蛋白A和D (SP-A, SP-D)对吸入病原体的先天宿主防御机制。这一认识不仅在普遍的呼吸道感染的背景下很重要,而且在与严重的全球生物威胁相关的情况下也很重要——抗生素耐药生物的出现;更致命的呼吸道病毒的进化和迅速传播;以及吸入病原体在生物恐怖主义行动中的潜在用途。有效的肺宿主防御需要早期识别微生物。在生物体沉积到呼吸道后,有一个清除病原体的关键机会窗口;延迟反应有利于感染。肺集合素在抵抗许多革兰氏阴性和阳性细菌及其内毒素、分枝杆菌、致病真菌和专性细胞内病原体(包括甲型流感(lAV)和其他潜在致命病毒)的先天防御中起着一线作用。肺集合物的先天防御特性依赖于它们的快速识别,在某些情况下,基于对高度保守的微生物表面成分(如lAV上的n -链高甘露糖聚糖和革兰氏阴性脂多糖(内毒素))的模式识别,它们可以中和吸入微生物。其他研究表明,缺乏肺集合的动物对微生物挑战的易感性显着增加。在小鼠过敏和感染模型中对重组截断SP-A和SP-D的研究提供了一种可能性,即通过吸入传递的这些蛋白的雾化形式可能在控制人类呼吸道感染、炎症和过敏方面具有治疗潜力。在这个项目中,一个高度协作和集中的项目小组使用互补的方法,包括x射线晶体学,诱变,光谱学,体外和体内分析,使用动物模型,专门针对收集物的先天反应,以及调节其活性的蛋白质,如KGF,对lAV和革兰氏阴性细菌的研究,以获得对其机理的理解,并协助设计潜在的基于收集素的治疗方法,提高其抗菌活性。

项目成果

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BARBARA A SEATON其他文献

BARBARA A SEATON的其他文献

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{{ truncateString('BARBARA A SEATON', 18)}}的其他基金

Collectins and Innate Defense against Inhaled Pathogens
集合素和针对吸入病原体的先天防御
  • 批准号:
    7695978
  • 财政年份:
    2009
  • 资助金额:
    $ 94.56万
  • 项目类别:
Collectins and Innate Defense against Inhaled Pathogens
集合素和针对吸入病原体的先天防御
  • 批准号:
    7924146
  • 财政年份:
    2009
  • 资助金额:
    $ 94.56万
  • 项目类别:
PHOSPHOLIPID HEAD GROUP RECOGNITION IN MEMBRANE BINDING PROTEIN ANNEXIN V
膜结合蛋白附件 V 中磷脂头基的识别
  • 批准号:
    6345252
  • 财政年份:
    2000
  • 资助金额:
    $ 94.56万
  • 项目类别:
PHOSPHOLIPID HEAD GROUP RECOGNITION IN MEMBRANE BINDING PROTEIN ANNEXIN V
膜结合蛋白附件 V 中磷脂头基的识别
  • 批准号:
    6478976
  • 财政年份:
    2000
  • 资助金额:
    $ 94.56万
  • 项目类别:
PHOSPHOLIPID HEAD GROUP RECOGNITION IN MEMBRANE BINDING PROTEIN ANNEXIN V
膜结合蛋白附件 V 中磷脂头基的识别
  • 批准号:
    6206447
  • 财政年份:
    1999
  • 资助金额:
    $ 94.56万
  • 项目类别:
CA BRIDGING MECHANISM & PHOSPHOLIPID HEAD GROUP RECOGNITION IN ANNEXIN V
CA桥接机制
  • 批准号:
    6123287
  • 财政年份:
    1998
  • 资助金额:
    $ 94.56万
  • 项目类别:
ANNEXIN CRYSTAL STRUCTURES AND MEMBRANE INTERACTIONS
膜联蛋白晶体结构和膜相互作用
  • 批准号:
    6476516
  • 财政年份:
    1990
  • 资助金额:
    $ 94.56万
  • 项目类别:
ANNEXIN CRYSTAL STRUCTURES AND MEMBRANE INTERACTIONS
膜联蛋白晶体结构和膜相互作用
  • 批准号:
    2182572
  • 财政年份:
    1990
  • 资助金额:
    $ 94.56万
  • 项目类别:
ANNEXIN CRYSTAL STRUCTURE AND PHOSPHOLIPID INTERACTION
膜联蛋白晶体结构和磷脂相互作用
  • 批准号:
    3468143
  • 财政年份:
    1990
  • 资助金额:
    $ 94.56万
  • 项目类别:
ANNEXIN CRYSTAL STRUCTURES AND MEMBRANE INTERACTIONS
膜联蛋白晶体结构和膜相互作用
  • 批准号:
    2444753
  • 财政年份:
    1990
  • 资助金额:
    $ 94.56万
  • 项目类别:

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