Novel Innate Immune Genes and Asthma

新型先天免疫基因与哮喘

基本信息

批准号：
7977187
负责人：
Jenny P Ting
金额：
$ 30.99万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
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：
2009-03-01 至 2013-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7977187
关键词：
A Mouse ATP phosphohydrolase Acute Adult Affect Allergens Aloral Animal Model Animals Antigens Apoptotic Asthma Bacteria Basic Science Binding Binding Proteins Biochemical Breathing Caspase-1 Cathepsins B Cell Adhesion Molecules Cell Line Cells Characteristics Childhood Clinical Complex Data Disease Disease Resistance Endotoxins Enzymes Exhibits Extravasation Family Family member Gene Family Genes Genomics Goals Human Immune Immune response Immune system Immunobiology Immunologics In Vitro Individual Infection Inflammation Inflammatory Response Interleukin-1 Interleukin-18 Klebsiella pneumonia bacterium Leucine Leucine-Rich Repeat Mediating Mining Modeling Mus NF-kappa B Names Necrosis Nucleotides Pathway interactions Phosphorylation Phosphotransferases Plants Process Production Property Protein Binding Domain Proteins Proteoglycan Pyroglyphidae Relative (related person)Reporting Role Sampling Sputum Subgroup System T-Lymphocyte Translating Walkers Work asthmatic patient chemokine combat drug discovery genetic linkage in vivo macrophage marenostrin novel pathogen procaspase-1 protein function protein structure pyroglyphid receptor reconstitution research study response vpr Genes

项目摘要

We recently discovered the CATERPILLER family which share structural similarities with the NB-LRR (nucleotide-binding, leucine-rich repeat) super-family of disease resistance (R) proteins that constitutes the plant immune system. In the animal kingdom, this family is also known as NOD or NLR. The clinical importance of this family is underscored by the genetic linkage of family members to a number of immunologic disorders. Among the human gene family members, several of these appear to mediate negative regulatory function in controlling an overzealous inflammatory response. Most notable is the Monarch-1 protein which blocks the function of NF-kB inducing kinase (NIK). Inhibition of NIK reduces the expression of an array of chemokines with relevance in asthma. Gene profiling of induced sputum from mildly asthmatic individuals suggests that the Monarch-1 gene is reduced in these individuals relative to controls, supporting the inhibitory role of this gene during inflammation. Another group of family members regulates IL-1 production. Most notable among these is cryopyrin which mediates formation of the inflammasome complex upon stimulation with a number of inducers. The inflammasome complex is required for procaspase 1 processing to mature caspase 1. In turn, caspase-1 is required for the processing of pro-IL-1 and pro-IL-18 to their mature forms. IL-1 and IL-18 are respectively important in inflammation and TH2 skewing. Cryopyrin is also important in mediating macrophage necrosis which exacerbates inflammation. Thus there are compelling reasons to believe that Monarch-1 and cryopyrin have crucial roles in asthma, however there is no in vivo data to indicate that this is the case. Furthermore we have shown that both of these proteins are ATP-binding proteins, and they exhibit ATPase activity, thus providing ways to modulate their function, which might be important leads to drug discovery. The goals of this proposal are: (1) To study the relevance of Monarch-1 in three animal models of asthma (OVA-induced, endotoxin, and house dust mite and delineate the biochemical effects of Monarch-1 in vivo and ex vivo. (2) To study the relevance of cryopyrin and a cryopyrin-adaptor (ASC) in asthma. (3) To study and identify factors which modulate the nucleotide-binding properties and ATPase function of Monarch-1 and cryopyrin.

我们最近发现了与NB-LRR共享结构相似性的Caterpiller家族（核苷酸结合，富含亮牙植物免疫系统。在动物界，这个家庭也被称为点头或NLR。临床这个家庭的重要性被家庭成员的遗传联系强调了免疫疾病。在人类基因家族成员中，其中一些似乎是在调解负责控制过度狂热反应的负调节功能。最值得注意的是君主-1蛋白阻断NF-KB诱导激酶（NIK）的功能。抑制NIK减少与哮喘相关的一系列趋化因子的表达。诱导痰的基因分析从轻度哮喘的个体中表明，这些个体中的君主-1基因减少了相对于对照，支持该基因在炎症过程中的抑制作用。另一组家庭成员调节IL-1的生产。其中最值得注意的是冷冻蛋白，它介导许多诱导剂刺激后的炎性体复合物。炎性体综合体是 procaspase 1处理至成熟caspase 1的要求。反过来，caspase-1需要将Pro-IL-1和Pro-IL-18处理成熟形式。 IL-1和IL-18在炎症和Th2偏斜。冷冻蛋白在介导巨噬细胞坏死中也很重要。加剧炎症。因此，有令人信服的理由相信Monarch-1和冷冻蛋白在哮喘中具有关键作用，但是没有体内数据可以表明情况。此外，我们已经表明，这两种蛋白质都是ATP结合蛋白，它们表现出来 ATPase活性，因此提供了调节其功能的方法，这可能是重要的导致药物发现。该提案的目标是：（1）研究三只动物中君主-1的相关性哮喘的模型（OVA诱导的，内毒素和房屋粉尘螨，并描绘出生化效应 Monarch-1体内和Ex Vivo。（2）研究冷冻蛋白和冷冻蛋白适应器（ASC）的相关性哮喘。（3）研究和确定调节核苷酸结合特性和ATPase的因素 Monarch-1和冷冻蛋白的功能。