Crohn's disease-associated NOD2 Mutants

克罗恩病相关的 NOD2 突变体

基本信息

批准号：
8069780
负责人：
XIAOJING MA
金额：
$ 1.16万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-01 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8069780
关键词：
Accounting Amino Acid Substitution Antigen-Presenting Cells B-Lymphocytes Binding Caspase Cells Clinical Research Crohn&apos s disease DNA Binding Data Development Disease Equilibrium Frameshift Mutation Gene Expression Gene Targeting Genes Goals Heterogeneous-Nuclear Ribonucleoproteins Human Immune Immune response Impairment Individual Infection Inflammation Inflammatory Inflammatory Response Interleukin-12 Intestinal Mucosa Leucine-Rich Repeat Link Mitogen-Activated Protein Kinases Mononuclear Mutation Myelogenous Nuclear Translocation Nucleotides Pathogenesis Pathology Patients Peptidoglycan Phosphorylation Positioning Attribute Production Property Protein Family Public Health Regulatory Pathway Research Running Signal Transduction T-Cell Activation Time Toll-like receptors base cytokine effective therapy gain of function human MAPK14 protein inhibitor/antagonist interleukin-23 leucine-rich repeat protein loss of function member microbial monocyte mutant novel response therapeutic target transcription factor

项目摘要

Nucleotide-binding oligomerization domain 2 (NOD2) is a monocyte-restricted member of a protein family critically involved in the activation of NF-KB in response to certain intracellular microbial infection. Dysfunctional mutations in the NOD2 gene underline the occurrence of inflammatory bower disease (IBD) in a substantial group of patients with Crohn's disease (CD). CD is characterized by an exaggerated T helper I (Thl)-type immune response. There are three most common mutations in the NOD2 gene associated with CD: an insertion of a C at nucleotide position 3020, designated 3020insC, which results in a frame shift mutation and the deletion of the terminal leucine-rich repeats (LRR) of the protein, and two amino acid substitution mutants also in the LRR region: R702W and G908R. Recent human clinical studies revealed defective IL-IO production in the mononuclear cells of CD patients homozygous for 3020insC. IL-lO is a critical immunoregulatory cytokine produced by antigen-presenting cells and activated T and B lymphocytes. The chronically impaired IL-lO production in these CD patients may contribute to persistent inflammation in the intestinal mucosa. Our own data indicate that, in contrast to the prevalent view, 3020insC is not simply a loss-of-function mutant. Instead, it can act as an inhibitor of IL-lO production. Furthermore, we have detected direct interactions between 3020insC with p38 mitogen-activated protein kinase (MAPK) and heterogeneous nuclear ribonucleoprotein Al (hnRNP AI), which we identified as a novel and constitutive transcription factor for IL-lO. 3020insC targets the DNA-binding activity of hnRNP Al by inhibiting its phosphorylation and nuclear translocation. Most importantly, we have confirmed that the phosphorylation of hnRNP Al and DNA-binding activity are indeed impaired in 3020insC-CD patients. In addition, we have identified for the first time a novel activity of the R702W and G908R mutants: they can stimulate and enhance IL-12/IL-23 gene expression. We hypothesize that the acquired property of 3020insC as an IL-lO inhibitor may result in chronically impaired IL-IO levels, whereas the R702W and G908R mutations may make individuals more prone to produce elevated levels of IL-12 and IL-23 in the myeloid compartment. In all, these three mutations cause either impairment of regulatory mechanisms or inappropriate proinflammatory cytokine production, which, combined with other contributory factors, contribute to homeostatic imbalance and persistent inflammation in the intestinal mucosa over time leading to the development and pathogenesis of CD. We propose to investigate the mechanisms whereby R702W and G908R regulate IL-12/IL-23 gene expression.

核苷酸结合寡聚结构域2（NOD2）是蛋白质家族的单核细胞限制成员针对某些细胞内微生物感染的响应，与NF-KB的激活至关重要。 NOD2基因中功能失调的突变强调了A炎症性托管疾病（IBD）的发生大量的克罗恩病患者（CD）。 CD的特征是夸张的T助手I （THL） - 型免疫反应。与CD相关的NOD2基因中，有三个最常见的突变：在核苷酸位置3020（指定3020INSC）插入C 蛋白质末端富含亮氨酸的重复序列（LRR）和两个氨基酸取代突变体的缺失也在LRR区域：R702W和G908R。最近的人类临床研究表明，CD患者的单核细胞中IL-IO的产生缺陷 3020INSC的纯合子。 IL-LO是由抗原呈递细胞产生的关键免疫调节细胞因子并活化的T和B淋巴细胞。这些CD患者的长期受损的IL-LO产生可能有助于肠粘膜持续的炎症。我们自己的数据表明，与普遍的视图3020INSC不仅是功能丧失的突变体。相反，它可以充当IL-lo的抑制剂生产。此外，我们已经检测到3020INSC与P38促丝分裂原激活之间的直接相互作用蛋白激酶（MAPK）和异质性核核糖核蛋白Al（HNRNP AI），我们将其识别为 IL-LO的新颖和本构转录因子。 3020INSC靶向HNRNP Al的DNA结合活性通过抑制其磷酸化和核易位。最重要的是，我们已经确认在3020INSC-CD患者中，HNRNP AL和DNA结合活性的磷酸化确实受损。在此外，我们首次确定了R702W和G908R突变体的新活性：它们可以刺激并增强IL-12/IL-23基因表达。我们假设3020INSC作为IL-LO抑制剂的获得性能可能会导致长期导致 IL-IO水平受损，而R702W和G908R突变可能会使个体更容易产生髓样室中IL-12和IL-23的水平升高。总之，这三个突变也会引起调节机制的损害或不适当的促炎性细胞因子产生的损害，该产生合并与其他有关因素有关，会导致稳态失衡和持续的炎症随着时间的流逝，肠粘膜导致CD的发育和发病机理。我们建议研究R702W和G908R调节IL-12/IL-23基因的机制表达。