Regulation of MD-2 function and expression

MD-2 功能和表达的调节

基本信息

批准号：
8493971
负责人：
JERROLD P WEISS
金额：
$ 33.24万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8493971
关键词：
Abbreviations Acids Acylation Affect Agonist Albumins Antigens Bacteria Binding Binding Proteins Binding Sites Biochemical Biological Buffers CCL4 gene CD14 gene Cells Complex Development Diet Disease Divalent Cations E protein Embryo Endotoxins Environment Epithelial Cells Epitopes Fatty Acids Glycolipids Gram-Negative Bacteria Gram-Negative Bacterial Infections Health Host Defense Human Hydrolase IL8 gene Immune Immune response Immunomodulators Infection Inflammation Inflammatory Response Interleukin-8 Invaded Irrigation Label Lead Ligands Lipid A Lipids Lipopolysaccharides Membrane Microbe Modeling Monoclonal Antibodies Mus Myelogenous Neisseria meningitidis Nonesterified Fatty Acids Nose Pathology Phosphate Buffer Phospholipids Phosphorylation Physiological Physiology Play Pneumonic Plague Proliferating Property Receptor Activation Recombinants Regulation Risk Role Saline Serum Albumin Signal Transduction Site Sodium Sodium Chloride Solutions Specific qualifier value Structure Surface Properties System TLR4 gene Toll-like receptors Translating Variant Virulence bactericidal permeability increasing protein in vivo insight kidney cell lipooligosaccharide lipopolysaccharide-binding protein mutant neutrophil novel novel strategies pathogen polyacrylamide gels polyhistidine protein E protein protein interaction public health relevance receptor response toll-like receptor 4

项目摘要

DESCRIPTION (provided by applicant): Host defense against many invading Gram-negative bacteria (GNB) depends upon innate immune recognition of endotoxin (E), unique, abundant and generally conserved glycolipids of GNB. Optimal TLR4- dependent responses are exquisitely sensitive and robust, but also self-limited. How this is normally achieved and why regulation of TLR4 activation may go awry under various patho-physiological conditions is incompletely known. The most potent inflammatory responses to E require certain canonical structural features of E and ordered protein-E and protein-protein interactions involving the LPS-binding protein (LBP), CD14, MD-2, and Toll-like receptor (TLR) 4. MD-2 plays an essential role in regulation of TLR4 activation by E, by bridging recognition of E, normally initiated by LBP and CD14, to receptor activation or antagonism. Our identification and characterization of monomeric E.MD-2 complexes as potent TLR4 agonists or antagonists, depending on E and/or MD-2 structure, have clearly demonstrated that it is the properties of the E.MD-2 complex, not E alone, that specifies TLR4 activation or receptor occupancy without activation. The unique structural and functional properties of these complexes suggest novel approaches to investigate how endotoxin induces TLR4 activation, how differences in E structure can dictate differences in TLR4 responsiveness, and how these new mechanistic insights may be translated to the development of novel TLR4-directed immunomodulators. Growing evidence of a broader array of molecules that can act as TLR4 agonists or antagonists, including host and/or diet-derived lipids, suggest many other circumstances in which the regulation or dysregulation of MD-2/TLR4 function could be pivotal in host physiology and patho-physiology. We will make use of novel synthetic, biochemical, structural biological, and functional approaches (e.g., metabolically labeled native and synthetic E and lipid A variants, recombinant wild-type and mutant human E-binding proteins and TLR4 ectodomain, monoclonal antibodies, models of airway infection and inflammation) to: 1) Further define the structural properties of ligands that promote binding to MD-2 and the action of ligand.MD-2 complexes as TLR4 agonists or antagonists; 2) Define more specifically the structural properties of E.MD-2 complexes that activate TLR4; and 3) Better define in vivo actions in the murine airway of wt and variant E(lipdA).Md-2.

描述（由申请人提供）：宿主防御许多入侵的革兰氏阴性细菌（GNB）取决于对内毒素（E）的先天免疫识别，独特的，丰富的，通常保守的GNB糖脂。最佳的TLR4-依赖性响应非常敏感且健壮，但也具有自限性。通常如何在各种病态生理条件下进行TLR4激活的调节可能会出现问题。 The most potent inflammatory responses to E require certain canonical structural features of E and ordered protein-E and protein-protein interactions involving the LPS-binding protein (LBP), CD14, MD-2, and Toll-like receptor (TLR) 4. MD-2 plays an essential role in regulation of TLR4 activation by E, by bridging recognition of E, normally initiated by LBP and CD14, to受体激活或拮抗作用。根据E和/或MD-2结构，我们对单体E.MD-2复合物作为有效的TLR4激动剂或拮抗剂的鉴定和表征清楚地表明，它是E.MD-2复合物的特性，而不是单独的E，它指定了TLR4激活或受体占用者而没有激活而指定的。这些复合物的独特结构和功能特性提出了新的方法来研究内毒素如何诱导TLR4激活，E结构中的差异如何决定TLR4响应性的差异以及如何将这些新的机械洞察力转化为新型TLR4指导免疫调节剂的发展。越来越多的分子可以充当TLR4激动剂或拮抗剂的越来越多的证据，包括宿主和/或饮食衍生的脂质，这表明许多其他情况在许多其他情况下，MD-2/TLR4功能的调节或失调可能在宿主生理学和病理生理学中可能是关键的。我们将利用新型的合成，生化，结构生物学和功能方法（例如，具有代谢标记的天然和合成E和脂质A的变异，重组野生型和突变的人E型和突变的人E-结合蛋白以及TLR4蛋白质以及TLR4成分，单位抗体，单位抗体，结构性构成，模型，体重构成，体积构成，体积构成，体积构成了体积的融合。促进与MD-2结合的配体以及Gimand.md-2复合物作为TLR4激动剂或拮抗剂的作用； 2）更具体地定义激活TLR4的E.MD-2复合物的结构特性； 3）更好地定义了WT和变体E（LIPDA）的鼠气中的体内作用.MD-2。

项目成果

期刊论文数量（27）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The cationic amphiphile 3,4-bis(tetradecyloxy)benzylamine inhibits LPS signaling by competing with endotoxin for CD14 binding.

DOI：
10.1016/j.bcp.2010.06.019
发表时间：
2010-12-15
期刊：
Biochemical pharmacology
影响因子：
5.8
作者：
Piazza M;Calabrese V;Baruffa C;Gioannini T;Weiss J;Peri F
通讯作者：
Peri F

Evidence of a specific interaction between new synthetic antisepsis agents and CD14.

DOI：
10.1021/bi901601b
发表时间：
2009-12-29
期刊：
BIOCHEMISTRY
影响因子：
2.9
作者：
Piazza, Matteo;Yu, Liping;Teghanemt, Athmane;Gioannini, Theresa;Weiss, Jerrold;Peri, Francesco
通讯作者：
Peri, Francesco

Hemin and a metabolic derivative coprohemin modulate the TLR4 pathway differently through different molecular targets.