Regulation of heme uptake in intestinal epithelial cells

肠上皮细胞血红素摄取的调节

• 批准号: 7190046
• 负责人: Aliye Uc
• 金额: $ 7.16万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-01 至 2008-11-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7190046
• 关键词: Adenoviruses; Affinity Chromatography; Apical; Award; Binding; Bioavailable; Biological Models; Blood Transfusion; Brush Border; Caco-2 Cells; Canis familiaris; Caveolae; Cell Communication; Cell Fractionation; Cell Line; Cell model; Cells; Cholesterol; Clathrin; Complement; Curcumin; Cytosol; Data; Diet; Disease; Duct (organ) structure; Electron Microscopy; Endocytosis; Endopeptidases; Enterocytes; Environment; Enzymes; Epithelial Cells; Equilibrium; Erythroid; Family suidae; Free Radicals; Funding; Goals; Golgi Apparatus; Grant; Heme; Heme Iron; Hemopexin; Hepatocyte; Hereditary hemochromatosis; Human; Injury; Intestinal Absorption; Intestinal Mucosa; Intestines; Investigation; Iowa; Iron; Iron Overload; Iron deficiency anemia; Label; Laboratories; Life; Meat; Mediating; Membrane; Membrane Microdomains; Membrane Proteins; Metabolism; Methionine; Mus; N-terminal; Nutritional; Organism; Pathway interactions; Peptide Hydrolases; Peptides; Physiology; Play; Process; Protein Databases; Proteins; Protoporphyrins; Rattus; Reactive Oxygen Species; Regulation; Research Personnel; Role; Scientist; Secondary to; Small Interfering RNA; Source; Spectrophotometry; Structure; Surface; Sus scrofa; Techniques; Testing; Toxic effect; Transfection; Trypsin; Universities; Work; absorption; apical membrane; base; basolateral membrane; brush border membrane; cold temperature; cytotoxic; heme oxygenase-1; heme receptor; heme-binding protein; inhibitor/antagonist; insight; programs; receptor; response; uptake

DESCRIPTION (provided by applicant): Project Summary: In this proposal, Dr. Aliye Uc is seeking a RO3 award to expand on her studies of intestinal heme uptake and transport mechanisms initiated under her KO8 grant, DK-63135. With the support of her KO8 funding, Dr. Uc started to examine heme-intestinal epithelial cell interactions through course work and laboratory investigations. Heme provides the majority of body's iron, but little is known about its intestinal absorption. Dr. Uc's observations so far suggest that enterocytes actively control heme uptake and transport, a phenomeon that can have an important role in the regulation of body iron stores. In the current R03 application, Dr. Uc proposes to begin investigating vesicular transport mechanisms involved in heme absorption and metabolism. Based on her preliminary data, Dr. Uc hypothesizes that heme is acquired by intestinal epithelial cells via an active and tightly regulated process that involves vesicular transport. Basolateral membrane heme uptake occurs via clathrin-dependent endocytosis; apical (lumen) heme is acquired via a membrane protein-dependent, cholesterol-sensitive, caveolar/lipid raft endocytosis. The specific aims are to: 1) Determine the vesicular transport mechanisms involved in intestinal heme uptake by using electron microscopy and cell fractionation techniques and colocalization with proteins that are trasported via clathrin or caveolae/lipid raft dependent pathways; 2) Determine the regulatory mechanisms involved in intestinal heme uptake by studying the role of a membrane heme binding protein and heme oxygenase-1. The current RO3 application, if approved will give Dr. Uc the opportunity to expand on her KO8-related goals and objectives as she approaches a full transition to an independent investigator status. The supportive environment at the University of Iowa will provide a perfect medium for Dr. Uc to accomplish her goal to become a fully independent clinician scientist. Relevance: Heme, found in red meat provides the majority of body's iron, but it can also cause injury by producing toxic free radicals. Because of its dual effects, intestinal heme absorption should be carefully regulated. However, it is not clear how intestinal epithelial cells take up heme from the diet or if they regulate its absorption. Defining intestinal heme uptake pathways will have a great impact in understanding disorders associated with iron overload (hereditary hemochromatosis, iron overload secondary to blood transfusions) and nutritional iron deficiency

描述(由申请人提供)： 项目概述：在这项提案中，Aliye UC博士正在寻求RO 3奖，以扩展她在KO8资助DK-63135下启动的关于肠道血红素吸收和运输机制的研究。在她的KO8基金的支持下，UC博士开始通过课程作业和实验室调查来研究血红素-肠道上皮细胞之间的相互作用。血红素提供了体内大部分的铁，但对其肠道吸收知之甚少。到目前为止，UC博士的观察表明，肠上皮细胞主动控制血红素的吸收和运输，这一现象可能在调节体内铁储存方面发挥重要作用。在目前的R03应用中，UC博士建议开始研究与血红素吸收和代谢有关的囊泡运输机制。根据她的初步数据，UC博士假设，血红素是由肠道上皮细胞通过涉及囊泡运输的活跃和严格调控的过程获得的。基侧膜血红素的摄取是通过依赖于笼蛋白的内吞作用进行的；顶端(腔)的血红素是通过膜蛋白依赖的、胆固醇敏感的空泡/脂筏内吞作用获得的。其具体目的是：1)通过电子显微镜和细胞分离技术以及与依赖于网状蛋白或小窝/脂筏转运的蛋白质的共定位，确定参与肠道血红素吸收的囊泡运输机制；2)通过研究膜血红素结合蛋白和血红素加氧酶-1的作用，确定参与肠道血红素吸收的调控机制。目前的R03申请如果获得批准，将使UC博士有机会在她接近完全过渡到独立研究员身份的过程中，扩展她与KO8相关的目标和目标。爱荷华大学的支持性环境将为UC博士实现她成为一名完全独立的临床科学家的目标提供一个完美的媒介。相关性：红肉中发现的血红素提供了人体大部分的铁，但它也可以通过产生有毒的自由基而造成伤害。由于它的双重作用，肠道中的血红素吸收应该受到仔细的调控。然而，目前还不清楚肠道上皮细胞是如何从饮食中摄取血红素的，也不清楚它们是否调节了它的吸收。明确肠道血红素摄取途径将对理解与铁超载(遗传性血色素沉着症、继发性输血引起的铁超载)和营养性铁缺乏相关的疾病有很大影响。