Genetic variation in the metal transporter ZIP8 and impact on the innate immune response in the gut

金属转运蛋白 ZIP8 的遗传变异及其对肠道先天免疫反应的影响

基本信息

批准号：
10310627
负责人：
Joanna Miller Peloquin Melia
金额：
$ 5.34万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10310627
关键词：
Adenoviruses Advisory Committees Affect American Antigens Arginine Attention Basic Science Biological Models Biology Body Weight CRISPR/Cas technology Citrobacter rodentium Clinical Colitis Complement Complex Crohn&apos s disease DNA Sequence Alteration Data Diet Dietary Intervention Digestive System Disorders Disease Disease Marker Distal part of ileum Down-Regulation Environmental Risk Factor Epithelial Epithelial Cells Equilibrium Foundations Functional disorder Future Gastroenterology Gastrointestinal tract structure Generations Genes Genetic Genetic Variation Genetic study Goals Health Heterozygote Homeostasis Homo Human Human Genome Hypertension Immune Immune response Impairment In Vitro Individual Inflammation Inflammatory Inflammatory Bowel Diseases Innate Immune Response Institution Interferon Type II Intestines Knock-in Mouse Literature Manganese Mediating Medicine Mentorship Metabolism Metals Methods Micronutrients Modeling Molecular Biology Molecular Immunology Mus Mutation Natural Immunity Nitric Oxide Nitric Oxide Synthase Obesity Oxidative Stress Parkinson Disease Pathogenesis Pathogenicity Patients Phenotype Physicians Positioning Attribute Predisposition Preparation Regulation Research Role Schizophrenia Scientist Severity of illness Signal Pathway Signal Transduction Single Nucleotide Polymorphism Stimulus System TNF gene Testing Tissues Training Training and Education Translational Research Ulcerative Colitis Variant Zinc Zinc deficiency antimicrobial peptide arginase career cell type cytokine cytotoxicity didactic education dietary disease diagnosis dysbiosis enteric infection experimental study genome wide association study host microbiota immunoregulation in vivo in vivo Model inflammatory disease of the intestine innate immune mechanisms innate immune pathways intestinal epithelium intestinal homeostasis knock-down mRNA Expression medical schools microbial microbiota mouse model novel overexpression pleiotropism professor tool zinc-binding protein

项目摘要

PROJECT ABSTRACT Inflammatory bowel diseases (IBD), including Crohn’s disease (CD) and ulcerative colitis, affect 1 in 200 Americans. IBD arises through a complex interplay of genetic, immune, microbial, and environmental factors disrupting intestinal homeostasis. There is a strong call from patients to study the role of diet-derived micronutrients in intestinal homeostasis. Recent genetic studies have focused attention on ZIP8 and the role of metal transport in CD through the discovery of an association between CD and a nonsynonymous single nucleotide polymorphism (SNP, rs13107325; Ala391Thr) in SLC39A8, the gene encoding ZIP8. This SNP has also been associated with six other diseases, including obesity and schizophrenia. Further, individuals with ZIP8 A391T shared a common fecal dysbiosis independent of disease diagnosis. The function of ZIP8 in the gut is not known, but in other cell types, ZIP8-mediated zinc transport negatively regulates NF-κB signaling by complexing with IKKβ and ZIP8-mediated manganese transport balances arginine metabolism away from nitric oxide synthase to reduce oxidative stress. Our preliminary data demonstrate that ZIP8 is increased in the inflamed terminal ileum of patients with CD and ZIP8 A391T impairs negative regulation of NF-κB signaling with reduced zinc transport. We have established two model systems for the studies proposed in this application: (i) ZIP8-knockdown in human ileal enteroids and (ii) a novel knock-in mouse with ZIP8 A393T, the mouse equivalent of the human variant. We hypothesize ZIP8-mediated metal transport regulates the innate immune response in intestinal epithelial cells, and this function is changed by ZIP8 A391T to promote CD pathogenesis. The aims of this project are (1) To establish the role of ZIP8 in intestinal epithelial cells in the innate immune response, (2) To study the effect of the CD-associated genetic variation in ZIP8 (A391T) on ZIP8 function in intestinal epithelial cells, and (3) To study the effect of the CD-associated genetic variation in ZIP8 on colitis susceptibility in a novel knock-in mouse model (ZIP8 A393T). The candidate is an Assistant Professor of Medicine at the Johns Hopkins School of Medicine in the Division of Gastroenterology with research and clinical training dedicated to IBD. The goal for this applicant is to use this project to enhance her molecular biology and immunology expertise and position her to build an independent career as a physician- scientist dedicated to studying the role of micronutrients in the pathophysiology of IBD. In addition to hands-on training and didactic education, the Training Plan includes strong mentorship from a Scientific Advisory Committee with diverse expertise in epithelial biology, metal biology, NF-κB signaling, oxidative stress, host- microbiota interactions and IBD, complemented by the strong support of the Hopkins Conte Digestive Diseases Basic and Translational Research Core Center and the institution.

项目摘要炎症性肠道疾病（IBD），包括克罗恩病（CD）和溃疡性结肠炎，有200份美国人。 IBD通过遗传，免疫，微生物和环境因素的复杂相互作用而产生破坏肠道稳态。患者有很强的呼吁研究饮食衍生的作用肠稳态中的微量营养素。最近的遗传研究集中于Zip8和通过发现CD和非同义单曲之间的关联，在CD中的金属传输 Slc39a8中的核苷酸多态性（SNP，RS13107325; ALA391THR），编码Zip8的基因。这个SNP具有还与其他六种疾病有关，包括肥胖和精神分裂症。此外，有个人 Zip8 A391T与疾病诊断无关共有常见的粪便障碍。 zip8在肠道尚不清楚，但在其他细胞类型中，Zip8介导的锌转运对NF-κB信号负面调节与IKKβ和Zip8介导的锰转运平衡精氨酸代谢相络氧化物合酶减少氧化应激。我们的初步数据表明，Zip8在 CD和ZIP8 A391T患者的发炎末端回肠会损害NF-κB信号的负调节锌运输减少。我们已经建立了两个模型系统，用于提出的研究应用：（i）人类回肠肠内的zip8-knockdown和（ii）用zip8 a393t的新型敲入小鼠，小鼠等同于人类变体。我们假设ZIP8介导的金属传输调节先天性肠上皮细胞中的免疫反应，Zip8 A391T改变了此功能以促进CD 发病。该项目的目的是（1）确定Zip8在肠上皮细胞中的作用先天免疫反应，（2）研究Zip8（A391T）对CD相关遗传变异的影响 Zip8在肠上皮细胞中的功能，（3）研究CD相关遗传变异在新型敲入小鼠模型（ZIP8 A393T）中结肠炎敏感性的Zip8。候选人是助手约翰·霍普金斯医学学院医学教授胃肠病学系专门针对IBD的研究和临床培训。该申请人的目标是使用该项目来增强她分子生物学和免疫学专业知识，并将她定位为建立独立职业科学家致力于研究微量营养素在IBD病理生理学中的作用。除了动手培训和教学教育，培训计划包括科学咨询的强大精神训练委员会具有上皮生物学，金属生物学，NF-κB信号，氧化应激，宿主的专业知识 Microbiota的相互作用和IBD，由Hopkins Conte消化疾病的大力支持完成基本和转化研究核心中心和机构。