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: 10852121
• 负责人: Joanna Miller Peloquin Melia
• 金额: $ 5.72万
• 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/10852121
• 关键词: Advisory Committees; Affect; American; Antigens; Attention; Basic Science; Biological Models; Biology; Complement; Complex; Crohn' s disease; Cytoplasm; DNA Sequence Alteration; Data; Dedications; Diet; Digestive System Disorders; Discipline; Disease; Distal part of ileum; Environmental Risk Factor; Epithelial Cells; Epithelium; Functional disorder; Gastroenterology; Gastrointestinal tract structure; Genes; Genetic; Genetic Variation; Genetic study; Goals; Homeostasis; Human; Immune; Immunology; In Vitro; Individual; Inflammation; Inflammatory Bowel Diseases; Innate Immune Response; Institution; Manganese; Mediating; Medicine; Mentorship; Metals; Microbiology; Micronutrients; Molecular Biology; Molecular Genetics; Mutation; Obesity; Pathogenesis; Pathogenicity; Patients; Physicians; Positioning Attribute; Regulation; Research Training; Role; Schizophrenia; Scientist; Signal Transduction; Single Nucleotide Polymorphism; Techniques; Training; Training and Education; Translational Research; Ulcerative Colitis; Zinc; apical membrane; career; cell type; clinical training; didactic education; dietary; disease diagnosis; dysbiosis; host microbiota; in vitro Model; in vivo Model; intestinal epithelium; intestinal homeostasis; medical schools; microbial; professor

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 into the cytoplasm results in negative regulation of NF-κB signaling. Our preliminary data demonstrate that ZIP8 is increased in the inflamed terminal ileum of patients with CD and localizes to the apical membrane in intestinal epithelial cells. We have established a model system using ileal enteroids to study ZIP8 biology. We hypothesize ZIP8 and ZIP8- mediated zinc transport regulates the innate immune response and host-microbiota interaction 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 CD-associated genetic variation in ZIP8 (A391T) on ZIP8 function in intestinal epithelial cells, and (3) To examine the role of ZIP8 in host-microbiota interactions. We will accomplish these aims by molecular genetics and microbiology techniques using human ileal enteroids as the in vitro model system. 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 short-term goal for this applicant is to use this project to enhance her molecular biology, immunology, and microbiology expertise and position her to build an independent career as a physician-scientist merging these disciplines to study 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, microbiology, zinc biology, NF-κB signaling, 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 人 200 名美国人。 IBD 是通过遗传、免疫、微生物和环境的复杂相互作用而产生的 破坏肠道稳态的因素。患者强烈呼吁研究饮食来源的作用 肠道稳态中的微量营养素。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）中的核苷酸多态性（SNP，rs13107325；Ala391Thr）。该 SNP 有 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 ZIP8 A391T 具有共同的粪便生态失调，与疾病诊断无关。 ZIP8的功能 肠道尚不清楚，但在其他细胞类型中，ZIP8 介导的锌转运到细胞质中会导致阴性结果 NF-κB 信号传导的调节。我们的初步数据表明，ZIP8 在发炎的终端中增加 CD 患者的回肠并定位于肠上皮细胞的顶膜。我们有 使用回肠肠类建立了模型系统来研究 ZIP8 生物学。我们假设 ZIP8 和 ZIP8- 介导的锌转运调节肠道内的先天免疫反应和宿主-微生物群相互作用 ZIP8 A391T 改变了这种功能，促进 CD 发病。本次活动的目的 项目包括 (1) 确定 ZIP8 在肠上皮细胞中在先天免疫反应中的作用，(2) 研究 ZIP8 (A391T) 中与 CD 相关的遗传变异对肠上皮中 ZIP8 功能的影响 (3) 研究 ZIP8 在宿主-微生物群相互作用中的作用。我们将通过以下方式实现这些目标 使用人回肠肠类作为体外模型系统的分子遗传学和微生物学技术。这 候选人是约翰霍普金斯大学医学院的医学助理教授 胃肠病学，致力于 IBD 的研究和临床培训。该申请人的短期目标是 利用这个项目来增强她的分子生物学、免疫学和微生物学专业知识，并为她定位 建立作为一名医师科学家的独立职业，融合这些学科来研究 IBD 病理生理学中的微量营养素。除了实践培训和教学教育外， 培训计划包括来自具有不同专业知识的科学咨询委员会的强有力指导 上皮生物学、微生物学、锌生物学、NF-κB信号传导、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基础和转化中心的大力支持 研究核心中心和机构。

项目成果

Crohn's Disease-Associated Pathogenic Mutation in the Manganese Transporter ZIP8 Shifts the Ileal and Rectal Mucosal Microbiota Implicating Aberrant Bile Acid Metabolism.

• DOI: 10.1093/ibd/izae003
• 发表时间: 2024-01
• 期刊: Inflammatory bowel diseases
• 影响因子: 4.9
• 作者: Kristi Briggs;Vartika Tomar;Nicholas Ollberding;Y. Haberman;A. Bourgonje;Shixian Hu;Lara Chaaban;L. Sunuwar;R. Weersma;L. Denson;Joanna Melia