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

• 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
• 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' 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

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1/200 美国人IBD是由遗传、免疫、微生物和环境因素复杂的相互作用引起的 破坏肠道内稳态有一个强烈的呼吁，从病人研究的作用，饮食来源的 微量营养素在肠道内稳态中的作用。最近的遗传学研究将注意力集中在ZIP 8和 通过发现CD和非同义单核苷酸之间的关联， SLC 39 A8（编码ZIP 8的基因）中的核苷酸多态性（SNP，rs 13107325; Ala 391 Thr）。这个SNP 还与其他六种疾病有关，包括肥胖症和精神分裂症。此外，个人与 ZIP 8 A391 T具有共同的粪便微生态失调，与疾病诊断无关。ZIP 8在 目前尚不清楚在肠道中的作用，但在其他细胞类型中，ZIP 8介导的锌转运通过以下途径负调控NF-κB信号传导： 与IKKβ和ZIP 8介导的锰转运复合平衡精氨酸代谢远离氮 氧化物合酶以减少氧化应激。我们的初步数据表明，ZIP 8在 CD和ZIP 8 A391 T患者的末端回肠发炎损害NF-κB信号传导的负调节 减少了锌的运输。我们已经建立了两个模型系统的研究建议，在这一点上， 应用：（i）人回肠类肠中的ZIP 8敲低和（ii）具有ZIP 8 A393 T的新型敲入小鼠， 相当于人类变异的小鼠。我们假设ZIP 8介导的金属转运调节先天性 肠上皮细胞中的免疫应答，并且该功能被ZIP 8 A391 T改变以促进CD 发病机制本研究的目的是：（1）确定ZIP 8在肠上皮细胞中的作用， （2）研究ZIP 8（A391 T）中CD相关的遗传变异对先天免疫应答的影响， ZIP 8在肠上皮细胞中的功能，以及（3）研究CD相关的遗传变异在肠上皮细胞中的作用。 ZIP 8对新型基因敲入小鼠模型（ZIP 8 A393 T）中结肠炎易感性的影响。候选人是助理 约翰霍普金斯医学院胃肠病学系医学教授， 致力于IBD的研究和临床培训。这个申请人的目标是利用这个项目来提高她的 分子生物学和免疫学专业知识，并定位她建立一个独立的职业生涯作为一个医生- 致力于研究微量营养素在IBD病理生理学中的作用的科学家。除了动手 培训和教学教育，培训计划包括来自科学顾问的强大指导 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，并得到霍普金斯康特消化疾病中心的大力支持 基础和转化研究核心中心和机构。