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：
10614435
负责人：
Joanna Miller Peloquin Melia
金额：
$ 17.17万
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 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10614435
关键词：
Adenoviruses Advisory Committees Affect American Antigens Arginine Attention Basic Science Biological Models Biology Body Weight CRISPR/Cas technology Citrobacter rodentium Colitis Complement Complex Conserved Sequence Crohn&apos s disease DNA Sequence Alteration Data Dedications Diet Dietary Intervention Digestive System Disorders Disease Disease Marker Distal part of ileum Down-Regulation Environmental Risk Factor Epithelial Cells Epithelium 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 Training 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 clinical training cytokine cytotoxicity didactic education dietary disease diagnosis dysbiosis enteric infection experimental study genome wide association study genome-wide analysis gut inflammation host microbiota immunoregulation in vivo in vivo Model 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.

项目摘要炎症性肠病 (IBD)，包括克罗恩病 (CD) 和溃疡性结肠炎，影响每 200 人中就有 1 人美国人 IBD 是通过遗传、免疫、微生物和环境因素的复杂相互作用而产生的。患者强烈呼吁研究饮食来源的作用。最近的遗传学研究将注意力集中在 ZIP8 及其作用上。通过发现 CD 和非同义单链之间的关联来研究 CD 中的金属传输 SLC39A8（编码 ZIP8 的基因）中存在核苷酸多态性（SNP，rs13107325；Ala391Thr）。还与其他六种疾病有关，包括肥胖症和精神分裂症。 ZIP8 A391T 具有与疾病诊断无关的常见粪便生态失调。肠道尚不清楚，但在其他细胞类型中，ZIP8 介导的锌转运通过以下方式负调节 NF-κB 信号传导：与 IKKβ 和 ZIP8 介导的锰转运复合，平衡精氨酸代谢，远离硝酸我们的初步数据表明，ZIP8 在体内增加。 CD 和 ZIP8 A391T 患者发炎的回肠末端损害 NF-κB 信号传导的负调节我们为本文提出的研究建立了两个模型系统。应用：(i) 人类回肠肠类中的 ZIP8 敲除和 (ii) 一种带有 ZIP8 A393T 的新型敲入小鼠，我们勇敢地面对 ZIP8 介导的金属转运调节先天性。肠上皮细胞中的免疫反应，ZIP8 A391T 改变了这种功能以促进 CD 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) 中与 CD 相关的遗传变异对 ZIP8 在肠上皮细胞中的功能，以及 (3) 研究 CD 相关遗传变异对肠上皮细胞的影响 ZIP8 对新型敲入小鼠模型 (ZIP8 A393T) 结肠炎易感性的影响候选人是助理。约翰·霍普金斯大学医学院胃肠病学系医学教授致力于 IBD 的研究和临床培训该申请人的目标是利用该项目来增强她的能力。分子生物学和免疫学专业知识使她能够建立独立的医生职业生涯- 除了实践之外，科学家还致力于研究微量营养素在 IBD 病理生理学中的作用。培训和教学教育，培训计划包括来自科学顾问的强有力指导委员会在上皮生物学、金属生物学、NF-κB信号传导、氧化应激、宿主- 微生物群相互作用和 IBD，并得到霍普金斯孔特消化疾病中心的大力支持基础与转化研究核心中心及机构。