Targeting Mitochondrial Iron Metabolism in Inflammatory Bowel Disease
靶向炎症性肠病的线粒体铁代谢
基本信息
- 批准号:9757782
- 负责人:
- 金额:$ 15.89万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:Aconitate HydrataseAcuteAdenosine TriphosphateAffectAnimal ModelAntigensBiologyCarbonCell SurvivalCell modelCell physiologyCellsChelating AgentsChronicCitric Acid CycleClinicClinicalColitisColonConsumptionDevelopmentDietDietary IronDisease ProgressionEpithelialFunctional disorderGenerationsGerm-FreeGlucoseGoalsHistologicHomeostasisInflammation MediatorsInflammatory Bowel DiseasesInflammatory ResponseInflammatory disease of the intestineIntakeIntestinesIronIron Chelating AgentsIron ChelationKnockout MiceKnowledgeLabelLaboratoriesLeadLipidsMacronutrients NutritionMediatingMediator of activation proteinMentorsMetabolismMicronutrientsMitochondriaMitochondrial ProteinsModelingMucous MembraneMusNutrientOxidative StressPathogenesisPatientsPhysiologicalPlayPopulationPositioning AttributePredispositionPreventionPrevention strategyProductionProstateProteinsProteomicsQuality of lifeRadioactiveRattusReactive Oxygen SpeciesReagentResearchResearch PersonnelRoleSeveritiesSodium Dextran SulfateSulfurSupporting CellSystemTestingTissuesTrainingTransgenic MiceTricarboxylic Acidsbasecareercareer developmentdysbiosisgut microbiotahost microbiotaimprovedin vitro Modelinterestintestinal epitheliumiron (III) reductaseiron metabolismiron supplementiron supplementationmicrobiotamitochondrial dysfunctionmitochondrial metabolismmouse modelnovelnovel strategiesoverexpressionpreservationpreventpublic health relevanceresponseuptake
项目摘要
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
线粒体功能障碍是炎症性肠病(IBD)的早期标志。在健康的细胞中,
线粒体消耗营养并产生大部分能量。然而,在炎症组织的细胞中,
能量由线粒体产生,营养物质被重组为构建块,以更好地支持细胞
生存迄今为止,广泛的研究集中在常量营养素的变化和影响上,
葡萄糖和脂质在炎症组织中的作用,但对微量营养素的作用知之甚少,
铁对IBD铁在线粒体产生活性氧(ROS)中是必不可少的,
for cell细胞survival生存.铁也是线粒体产生铁硫簇(ISC)所必需的,
关键的细胞过程,包括三羧酸(TCA)循环。长期目标是了解铁
与线粒体相互作用并促进IBD的疾病进展。候选人假设,
线粒体铁通过调节TCA循环和ROS的产生,是IBD发展的关键介质。
有几个障碍,使理解线粒体铁对细胞的影响,
肠道炎症难以研究,即合适的细胞和动物模型。这里的候选人
提出利用一组独特的模型:1)保持完整的铁运输系统的肠,
炎症反应; 2)一种新的肠上皮特异性过表达转基因小鼠模型
铁还原酶六跨膜上皮抗原4(STEAP 4),其具有增强的线粒体铁
3)一种新的和高度临床相关的人源化IL 10-/-
慢性结肠炎小鼠模型。候选人将专注于以下具体目标:1)描述
铁对IBD线粒体代谢的影响; 2)了解STEAP 4在线粒体铁代谢中的作用
3)表征线粒体铁失调是否有助于IBD相关的内稳态;
生态失调实现这些目标将提供一个机制性的解释和新的目标,为预防或
IBD的治疗
建议书中的目标1将建立在导师实验室对铁的优势和兴趣的基础上
肠道内的新陈代谢。此外,实现目标1将允许充分的培训,以利用小说
研究线粒体铁对TCA循环和铁利用的影响。这将有助于
候选人的研究生涯向独立调查员职位的过渡。实现目标
2和3将使候选人了解铁还原酶STEAP 4在肠上皮细胞中的作用。
生物学和宿主线粒体微量营养素与肠道微生物群的相互作用。
总之,这一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,
它不仅有助于代谢和肠道微生物群研究,而且有助于了解IBD的发病机制。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('Xiang Xue', 18)}}的其他基金
Profiling iron-regulated metabolic reprogramming for nucleotide biosynthesis in colon tumors
分析结肠肿瘤中核苷酸生物合成的铁调节代谢重编程
- 批准号:
10408034 - 财政年份:2020
- 资助金额:
$ 15.89万 - 项目类别:
Profiling iron-regulated metabolic reprogramming for nucleotide biosynthesis in colon tumors
分析结肠肿瘤中核苷酸生物合成的铁调节代谢重编程
- 批准号:
10629363 - 财政年份:2020
- 资助金额:
$ 15.89万 - 项目类别:
Profiling iron-regulated metabolic reprogramming for nucleotide biosynthesis in colon tumors
分析结肠肿瘤中核苷酸生物合成的铁调节代谢重编程
- 批准号:
10202652 - 财政年份:2020
- 资助金额:
$ 15.89万 - 项目类别:
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