权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Manganese in Inflammatory Bowel Disease

锰在炎症性肠病中的作用

基本信息

批准号：
10604119
负责人：
Young Ah Seo
金额：
$ 35.1万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10604119
关键词：
Acute Adherent Culture Affect American Animals Biology CRISPR/Cas technology Ceramidase Chronic Consumption Crohn&apos s disease Data Dependence Development Diet Dietary Fiber Dietary Manganese Digestive System Disorders Disease Disease model Disease susceptibility Dose Environmental Risk Factor Enzymes Epithelial Cells Etiology Exhibits Family Fatty acid glycerol esters Food Future Genes Genetic Genetic Models Grain Health Homeostasis Human In Vitro Incidence Individual Inflammatory Inflammatory Bowel Diseases Intake Intestinal permeability Intestines Investigation Ions Iron Knock-in Mouse Knockout Mice Lead Lipids Manganese Meat Mediating Metals Micronutrients Minor Mitochondria Mus Mutant Strains Mice Mutation Normal Range Nutrient Nutritional Nuts Organoids Patients Plants Play Positioning Attribute Predisposition Production Reactive Oxygen Species Recommendation Research Resources Rice Role Single Nucleotide Polymorphism Sodium Dextran Sulfate Source Testing Ulcerative Colitis Variant Vegetables Zinc dextran sulfate sodium induced colitis dietary divalent metal epidemiology study genome wide association study gut inflammation high risk inhibitor insight intestinal epithelium manganese deficiency mouse model novel therapeutic target transcriptomics western diet

项目摘要

Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is a family of chronic inflammatory disorders of the gastrointestinal tract that affect over 3 million Americans. While genetic background clearly plays a role, environmental factors, especially dietary nutrients, have been suspected as triggers to contribute to the disease development. Identifying the direct causal mechanisms by which genetics and dietary nutrients coordinately influence IBD susceptibility may provide direct utility in uncovering both how the disease develops and how it may be treated in the future. Although genetic factors appear to play relatively minor roles in IBD, there is one particular association of single nucleotide polymorphism (SNP) with IBD that showed up at the top of a recent genome-wide association screen in IBD: a common variant in the manganese transporter SLC39A8 (p.Ala391Thr). We and others have shown that this transporter is critical for the incorporation of manganese (Mn), a micronutrient required for many enzymatic activities. The SLC39A8 A391T variant was shown in vitro to have reduced Mn incorporating function, and we made similar observations independently. These revelations hint toward alterations in Mn levels caused by diet or genetics, as contributing factors for IBD. Yet, Mn deficiency has traditionally been rare in humans due to its various dietary sources. Mn is abundant in plant-based foods, including whole grains, rice, nuts, and leafy vegetables, whereas animal-based foods lack this nutrient. Recent epidemiological studies have revealed >40% reduction in dietary Mn consumption in the past 15 years due to a Western diet characterized by high intakes of red meats, high fat foods, and refined grains. This data is congruent with the increasing incidence of IBD, and it supports an inverse relationship between nutritional Mn levels and IBD patients. However, we still have not established if there is a causal role of Mn in IBD and the mechanism by which Mn contributes to IBD. This project will define functional insight into the roles of dietary Mn and SLC39A8 that maintain intestinal health, thereby advancing research into the etiology of IBD. Our findings will pave the way for future research in individuals at high risk of IBD to provide dietary recommendations and therapeutic targets.

炎症性肠病 (IBD)，包括克罗恩病和溃疡性结肠炎，是一系列胃肠道慢性炎症性疾病，影响超过 300 万美国人。虽然遗传背景显然发挥了作用，但环境因素，尤其是饮食营养素，被怀疑是导致疾病发展的触发因素。确定遗传和膳食营养素协调影响 IBD 易感性的直接因果机制可能为揭示疾病如何发展以及未来如何治疗提供直接的帮助。尽管遗传因素似乎在 IBD 中发挥相对较小的作用，但单核苷酸多态性 (SNP) 与 IBD 之间存在一种特殊关联，该关联出现在最近 IBD 全基因组关联筛选的顶部：锰转运蛋白 SLC39A8 (p.Ala391Thr) 中的一种常见变异。我们和其他人已经证明，这种转运蛋白对于锰 (Mn) 的掺入至关重要，锰是许多酶活性所需的微量营养素。 SLC39A8 A391T 变体在体外被证明具有降低的 Mn 掺入功能，并且我们独立地进行了类似的观察。这些发现暗示饮食或遗传引起的锰水平变化是 IBD 的促成因素。然而，由于膳食来源多样，锰缺乏症在人类中历来很少见。植物性食品中含有丰富的锰，包括全谷物、大米、坚果和叶类蔬菜，而动物性食品则缺乏这种营养素。最近的流行病学研究表明，由于西方饮食以大量摄入红肉、高脂肪食物和精制谷物为特征，过去 15 年膳食锰消耗量减少了 40% 以上。该数据与 IBD 发病率的增加相一致，并且支持营养锰水平与 IBD 患者之间的负相关关系。然而，我们仍未确定 Mn 是否在 IBD 中起因果作用以及 Mn 促进 IBD 的机制。该项目将明确饮食中 Mn 和 SLC39A8 在维持肠道健康方面的作用，从而推进对 IBD 病因学的研究。我们的研究结果将为未来对 IBD 高风险个体的研究铺平道路，以提供饮食建议和治疗目标。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A neurodegeneration gene, WDR45, links impaired ferritinophagy to iron accumulation.

DOI：
10.1111/jnc.15548
发表时间：
2022-03
期刊：
Journal of neurochemistry
影响因子：
4.7
作者：
Aring L;Choi EK;Kopera H;Lanigan T;Iwase S;Klionsky DJ;Seo YA
通讯作者：
Seo YA

In vitro studies of manganese transport and homeostasis.

锰转运和稳态的体外研究。

DOI：
10.1016/bs.mie.2023.04.023
发表时间：
2023
期刊：
Methods in enzymology
影响因子：
0
作者：
Kim,Sangnam;Seo,YoungAh
通讯作者：
Seo,YoungAh

A small molecule redistributes iron in ferroportin-deficient mice and patient-derived primary macrophages.

DOI：
10.1073/pnas.2121400119
发表时间：
2022-06-28
期刊：
Proceedings of the National Academy of Sciences of the United States of America
影响因子：
11.1
作者：
通讯作者：

Genome-Wide Association Meta-Analysis of Individuals of European Ancestry Identifies Suggestive Loci for Sodium Intake, Potassium Intake, and Their Ratio Measured from 24-Hour or Half-Day Urine Samples.

对欧洲血统个体的全基因组关联荟萃分析确定了钠摄入量、钾摄入量的暗示位点，以及从 24 小时或半天尿液样本中测量的它们的比率。

DOI：
10.1093/jn/nxaa241
发表时间：
2020
期刊：
The Journal of nutrition
影响因子：
0
作者：
Kho,Minjung;Smith,JenniferA;Verweij,Niek;Shang,Lulu;Ryan,KathleenA;Zhao,Wei;Ware,ErinB;Gansevoort,RonT;Irvin,MargueriteR;Lee,JungEun;Turner,StephenT;Sung,Joohon;vanderHarst,Pim;Arnett,DonnaK;Baylin,Ana;Park,SungKy
通讯作者：
Park,SungKy

Transcriptome Analysis of the Cerebellum of Mice Fed a Manganese-Deficient Diet.