Regulation of heme uptake in intestinal epithelial cells

肠上皮细胞血红素摄取的调节

• 批准号: 7018313
• 负责人: Aliye Uc
• 金额: $ 7.38万
• 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 2008-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7018313
• 关键词: binding proteins; clathrin; electron microscopy; endocytosis; gastrointestinal absorption /transport; heme; heme oxygenase; intestinal mucosa; intracellular transport; iron metabolism; laboratory mouse; lipid raft; protein localization; radiotracer; reticulocytes

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）： 项目摘要：在这项提案中，Aliye Uc博士正在寻求RO 3奖，以扩大她在KO 8赠款DK-63135下启动的肠道血红素摄取和转运机制的研究。在KO 8基金的支持下，Uc博士开始通过课程和实验室研究来研究血红素-肠上皮细胞的相互作用。血红素提供了身体的大部分铁，但对它的肠道吸收知之甚少。到目前为止，Uc博士的观察表明，肠上皮细胞积极控制血红素的吸收和运输，这是一种在调节体内铁储存方面发挥重要作用的现象。在目前的R 03申请中，Uc博士建议开始研究血红素吸收和代谢中涉及的囊泡转运机制。根据她的初步数据，Uc博士假设血红素是由肠上皮细胞通过涉及囊泡运输的主动和严格调节的过程获得的。基底外侧膜血红素摄取通过网格蛋白依赖性内吞作用发生;顶端（管腔）血红素通过膜蛋白依赖性、胆固醇敏感性、小窝/脂筏内吞作用获得。具体目标是：1）通过使用电子显微镜和细胞分级技术以及与通过网格蛋白或小窝/脂筏依赖性途径转运的蛋白质的共定位来确定肠血红素摄取中涉及的囊泡转运机制; 2）通过研究膜血红素结合蛋白和血红素加氧酶-1的作用来确定肠血红素摄取中涉及的调节机制。目前的RO 3申请，如果获得批准，将使Uc博士有机会扩大她的KO 8相关目标和目的，因为她接近完全过渡到独立研究者的地位。爱荷华州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：在红肉中发现的血红素提供了人体大部分的铁，但它也会通过产生有毒的自由基而造成伤害。由于其双重作用，肠道血红素吸收应仔细调节。然而，目前尚不清楚肠上皮细胞如何从饮食中摄取血红素，或者它们是否调节血红素的吸收。确定肠道血红素摄取途径将对理解与铁过载（遗传性血色素沉着症，继发于输血的铁过载）和营养性铁缺乏相关的疾病产生重大影响