Targeting Mitochondrial Iron Metabolism in Inflammatory Bowel Disease

靶向炎症性肠病的线粒体铁代谢

• 批准号: 9757782
• 负责人: Xiang Xue
• 金额: $ 15.89万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9757782
• 关键词: Aconitate Hydratase; Acute; Adenosine Triphosphate; Affect; Animal Model; Antigens; Biology; Carbon; Cell Survival; Cell model; Cell physiology; Cells; Chelating Agents; Chronic; Citric Acid Cycle; Clinic; Clinical; Colitis; Colon; Consumption; Development; Diet; Dietary Iron; Disease Progression; Epithelial; Functional disorder; Generations; Germ-Free; Glucose; Goals; Histologic; Homeostasis; Inflammation Mediators; Inflammatory Bowel Diseases; Inflammatory Response; Inflammatory disease of the intestine; Intake; Intestines; Iron; Iron Chelating Agents; Iron Chelation; Knockout Mice; Knowledge; Label; Laboratories; Lead; Lipids; Macronutrients Nutrition; Mediating; Mediator of activation protein; Mentors; Metabolism; Micronutrients; Mitochondria; Mitochondrial Proteins; Modeling; Mucous Membrane; Mus; Nutrient; Oxidative Stress; Pathogenesis; Patients; Physiological; Play; Population; Positioning Attribute; Predisposition; Prevention; Prevention strategy; Production; Prostate; Proteins; Proteomics; Quality of life; Radioactive; Rattus; Reactive Oxygen Species; Reagent; Research; Research Personnel; Role; Severities; Sodium Dextran Sulfate; Sulfur; Supporting Cell; System; Testing; Tissues; Training; Transgenic Mice; Tricarboxylic Acids; base; career; career development; dysbiosis; gut microbiota; host microbiota; improved; in vitro Model; interest; intestinal epithelium; iron (III) reductase; iron metabolism; iron supplement; iron supplementation; microbiota; mitochondrial dysfunction; mitochondrial metabolism; mouse model; novel; novel strategies; overexpression; preservation; prevent; public health relevance; response; uptake

1. Project Summary Mitochondrial dysfunction is an early hallmark of inflammatory bowel disease (IBD). In healthy cells, mitochondria consume nutrients and generate most of the energy. However, in cells from inflamed tissue, less energy is produced by mitochondria, and nutrients are reorganized as building blocks to better support cell survival. To date, extensive studies have been focused on the changes and impact of macronutrients such as glucose and lipids in inflamed tissues, but much less is known about the contribution of micronutrients such as iron to IBD. Iron is essential in mitochondrial generation of reactive oxygen species (ROS), which is important for cell survival. Iron is also needed for mitochondria to produce iron-sulfur clusters (ISC) that support many critical cellular processes including tricarboxylic acid (TCA) cycle. The long-term goal is to understand how iron interacts with mitochondria and contributes to the disease progression of IBD. The candidate hypothesizes that mitochondrial iron is a critical mediator for the IBD development by regulating TCA cycle and ROS production. There have been several hurdles that have made understanding the effects of mitochondrial iron on the intestinal inflammation difficult to study, namely appropriate cell and animal models. Here the candidate proposes to utilize a set of unique models: 1) enteroids that keep an intact iron transport system and inflammatory response; 2) a novel transgenic mouse model with intestinal epithelium-specific overexpression of a ferrireductase six transmembrane epithelial antigen 4 (STEAP4), which has enhanced mitochondrial iron accumulation and increased susceptibility to colitis; 3) a novel and highly clinic-relevant humanized Il10-/- mouse model of chronic colitis. The candidate will focus on the following specific aims: 1) Characterize the effect of iron on mitochondrial metabolism in IBD; 2) Understand the role of STEAP4 in mitochondrial iron homeostasis in IBD; 3) Characterize if mitochondrial iron dysregulation contributes to IBD-associated dysbiosis. Accomplishing these goals will provide a mechanistic explanation and novel targets for prevention or treatment of IBD. Aim 1 in the proposal will build upon the strengths and interests of the mentors’ laboratories with respect to iron metabolism in the intestine. Moreover, accomplishing Aim 1 will allow the adequate training to utilize the novel enteroids to study the impact of mitochondrial iron on TCA cycles and the utilization of iron. This will aid the transition of the candidate’s research career toward an independent investigator position. Accomplishing Aims 2 and 3 will allow the candidate to understand the role of the ferrireductase STEAP4 in intestinal epithelial biology and the interaction of host mitochondrial micronutrients with the gut microbiota. Together, this proposal is not only critical for the candidate’s career development in the field of micronutrient metabolism and gut microbiota research, but also it will aid in understanding the pathogenesis of IBD.

1。项目摘要 线粒体功能障碍是健康细胞中炎症性肠病（IBD）的早期标志。 线粒体消耗营养，并在发炎组织中产生大部分能量。 能量是由米奇德里亚（Mitchondria）产生的，营养物质被重新化为基础，以更好地支持细胞 生存。 发炎组织中的葡萄糖和脂质物，但对微量营养素的贡献（例如 铁到IBD。 对于细胞生存也需要铁粒产生支持许多人的铁硫簇（ISC） 包括三羧酸（TCA）周期的关键细胞过程。 与线粒体相互作用，并有助于IBD的疾病进展。 线粒体铁是通过调节TCA周期和ROS产生的关键介体。 有几个障碍使线粒体铁对 肠道炎症困难tudy，即适当的细胞和动物模型。 提议利用一组独特的模型：1）保持完整的铁运输系统和 炎症反应； 2）具有特异性过表达的新型转基因小鼠模型 六跨膜上皮抗原4（step4）的六跨膜化合物（Step4）的含量增强了线粒体铁 累积和增加颜色的敏感性； 慢性结肠炎的小鼠模型。 铁对IBD的线粒体代谢的影响； 2） IBD中的稳态； 障碍。 治疗IBD。 在提案中的目标1基于导师实验室对铁的优势和利益 此外，在肠道中的代谢。 用于研究线粒体铁对TCA周期的影响和铁的利用。 候选人的研究职业过渡到独立的研究者 2和3将允许候选者在肠上皮中的效能运动员step4的作用 生物学和宿主线粒体微量营养素与肠道菌群的相互作用。 在一起，该建议不仅对候选人在微量营养素领域的职业发展至关重要 代谢和肠道菌群研究，但它也将有助于理解IBD的发病机理。