NOD-like Receptors in Intestinal Inflammation

肠道炎症中的 NOD 样受体

基本信息

批准号：
10447741
负责人：
Jenny P Ting
金额：
$ 35.34万
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：
2013
资助国家：
美国
起止时间：
2013-09-19 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10447741
关键词：
Adoptive Transfer Affect Animal Model Anti-Inflammatory Agents Attenuated Bacteria Bacteroides Binding CD4 Positive T Lymphocytes Cell Communication Cell membrane Cells Colitis Colon Colon Carcinoma Colonic inflammation Crohn&apos s disease Data Disease model Epithelial Epithelial Cells Family Family member Gene Deletion Gene Expression Genes Genetic Glycolysis Gnotobiotic Goals Homeostasis Human Immune Immune signaling Immunologic Receptors Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory Response Inflammatory Response Pathway Interferon Type II Intestines Lead Leucine-Rich Repeat Link MAP Kinase Gene Mediating Metabolic Pathway Metabolism Metagenomics Modeling Molecular Mucous Membrane Mus Myelogenous Myeloid Cells Natural Immunity Nucleotides Outcome Oxidative Phosphorylation Pathway interactions Patients Pattern Phenotype Population Proteins Publishing Role Sampling Severities Shapes Signal Pathway Signal Transduction Subgroup Supplementation T-Cell Activation T-Lymphocyte TNF gene TRAF6 gene TRIM25 gene Testing Tissues Ubiquitination Work cell type commensal microbes cytokine disease phenotype dysbiosis gut inflammation gut microbiome gut microbiota human genomics human tissue immune activation intestinal epithelium metabolomics microbial microbiome microbiota mouse model new therapeutic target novel pathogen prevent receptor screening sensor transcriptome sequencing ubiquitin ligase

项目摘要

ABSTRACT The discovery of innate immune receptors has revolutionized the field of innate immunity. An unexpected finding is that innate immune receptor are not only located on the cell membrane, but a majority of these are found intracellularly. This allows cells to detect intracellular perturbation from pathogen-associated molecular patterns (PAMPs) or from damage-associated molecular patterns (DAMPs). Our studies have revealed a novel roles of intracellular innate immune receptor in attenuating inflammation and shaping the microbiome during inflammatory bowel disease (IBD). The central hypothesis is that the bi-directional interplay of inhibitory intracellular innate receptors with the microbiome is a major contributing factor in IBD. Our proposal focuses on the intracellular NLR (nucleotide-binding domain, leucine-rich repeat containing protein, or NOD-like receptor) proteins. While NOD2 remains the most prominent in Crohns’ disease, we have focused on the role of other NLRs in colitis. We have data to show that several inhibitory NLR proteins strongly mitigate intestinal inflammation by reducing the activation of immune signaling pathway thus preventing an inflammatory cytokine response that is integral to colitis. This in turn can affect both innate and adaptive immune cells, as well as colon epithelial cells. We have also shown that these inhibitory NLRs affect the microbiome, partly by maintaining bacteria that can contain a pro-inflammatory response. Thus the first goal is to understand the bidirectional interaction of inhibitory NLR and the gut microbiota in mitigating gut inflammation in mice by working with Projects 2, 4 and the Animal Models Core A. Another over-arching goal is to assess the translational relevance of results obtained in mice to humans. Working with Project 3 and the Human Tissue and Genomics Core B, we will analyze patient-derived material to verify the significance of our findings in mice to inflammatory bowel disease patient samples.

抽象的先天免疫受体的发现彻底改变了先天免疫受体的领域。意外发现先天免疫受体不仅位于细胞膜上，而且其中大多数是细胞内发现。这使细胞可以检测与病原体相关分子的细胞内扰动图案（弹奏）或来自损伤相关的分子图案（湿）。我们的研究表明细胞内先天免疫受体在减弱炎症和塑造微生物组中的新作用在炎症性肠病（IBD）期间。中心假设是抑制性的双向相互作用具有微生物组的细胞内先天受体是IBD的主要促成因素。我们的建议重点细胞内NLR（核苷酸结合结构域，富含亮氨酸的重复蛋白或点头样受体）蛋白质。尽管Nod2仍然是克罗恩斯氏病中最突出的，但我们还是专注于其他 NLR在结肠炎中。我们有数据表明，几种抑制性NLR蛋白会大大减轻肠道通过减少免疫信号传导途径的激活来防止炎症，从而防止炎症细胞因子与结肠炎不可或缺的反应。反过结肠上皮细胞。我们还表明，这些抑制性NLR会影响微生物组，部分是由维持可能包含促炎反应的细菌。第一个目标是了解抑制性NLR和肠道菌群的双向相互作用在减轻小鼠肠道注射中的双向相互作用与项目2、4和动物模型核心A合作。A的另一个目标是评估在小鼠中获得的结果的转化相关性。与项目3和人体组织一起工作和基因组核心B，我们将分析患者衍生的材料，以验证我们发现在小鼠中的重要性炎症性肠病患者样品。