Aldosterone Activation of Trans-epithelial Iron Absorption in Human Colon

醛固酮激活人结肠跨上皮铁吸收

• 批准号: 9769726
• 负责人: Vazhaikkurichi M. Rajendran
• 金额: $ 18.75万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9769726
• 关键词: Address; Affect; Aldosterone; Animals; Apical; Arthralgia; Carcinoma; Carrier Proteins; Celiac Disease; Chairperson; Characteristics; Clinical Trials; Collaborations; Colon; Core Facility; Cytochromes b; DNA biosynthesis; Data; Diet; Dietary Iron; Disease; Distal; Duodenum; Epithelial; Epithelium; Excision; Experimental Models; Family Practice; Heme; Hemorrhage; Human; Hypoxia; In Vitro; Inflammatory; Ingestion; Intake; Intestines; Intravenous; Iron; Iron deficiency anemia; Knowledge; Large Intestine; Length; Letters; Measures; Mediating; Membrane; Messenger RNA; Metabolism; Myalgia; Nutrient; Nutrition Disorders; Organ; Organoids; Patients; Peptic Ulcer; Pharmaceutical Preparations; Process; Proteins; Pruritus; Rattus; Regulation; Reporting; Research; Respiration; Route; SLC11A2 gene; Site; Small Interfering RNA; Transactivation; Transfection; Ulcerative Colitis; Urticaria; absorption; analog; bariatric surgery; base; cytokine; design; epithelial Na+ channel; iron absorption; iron deficiency; iron supplement; knock-down; medical schools; metal transporting protein 1; protein expression; side effect; uptake; voltage clamp

PROJECT SUMMARY/ABSTRACT The aim of this project is to identify the aldosterone (“aldo”) activation of iron (Fe2+) absorption in a human colon. The duodenum is the primary site for iron absorption. Duodenal Fe2+ absorption is hampered in patients with celiac sprue and peptic ulcer diseases, during gastric bypass surgery, and in patients that develop iron deficiency and iron deficiency anemia (IDA). Coordinated regulation of apical divalent metal transporter-1 (DMT1) and basolateral ferroportin-1 (FPN1) mediate the trans-epithelial iron absorption. Although the duodenum is the primary site for iron absorption, both DMT1 and FPN1 are also expressed with decreasing levels along the entire length of the intestinal tract, including the colon. In general, hypoxia and iron deficiency up-regulate iron absorption, and DMT1 and FPN1 expression. We were pleasantly surprised during our preliminary studies, when we identified that aldosterone enhanced DMT1 and FPN1 expression, and increased iron absorption in a rat colon. Since “aldo” stimulates the epithelial Na+ channel (ENaC) in both rats and humans, we propose that “aldo” would also stimulate iron absorption by enhancing DMT1 and FPN1 expression in a human colon. Identification of the “aldo” enhanced colonic iron absorption would serve as an alternate site and distinct mechanism to stimulate iron absorption in patients with hampered duodenal iron absorption. Thus, we are proposing the following aims. Specific Aim-1 will identify and establish the iron transporters and iron absorption capacity of a normal human colon. We will accomplish this task by characterizing iron transporters and trans-epithelial iron absorption by measuring 59FeSO4 fluxes in epithelial layers and organoids; and by establishing trans-epithelial iron absorption requires coordinated regulation of apical (DMT1) and basolateral (FPN1) transporters by selective knockdown using siRNA transfection. Specific Aim-2 will address identifying the mechanisms to stimulate iron transporters and iron absorption in a normal human colon. This will be accomplished by establishing that “aldo” enhances iron transporters and trans- epithelial iron absorption and by identifying one or more pro-inflammatory cytokines that specifically up-regulate DMT1 and FPN1 expression, and iron absorption capacity in colonic epithelial layers and colonoids.

项目概要/摘要 该项目的目的是确定醛固酮 (“aldo”) 对人体铁 (Fe2+) 吸收的激活作用 冒号。十二指肠是吸收铁的主要部位。患者十二指肠 Fe2+ 吸收受到阻碍 患有乳糜泻和消化性溃疡疾病、胃绕道手术期间以及产生铁的患者 缺乏症和缺铁性贫血（IDA）。顶端二价金属转运蛋白-1的协调调控 (DMT1) 和基底外侧铁转运蛋白-1 (FPN1) 介导跨上皮铁吸收。虽然 十二指肠是铁吸收的主要部位，DMT1和FPN1的表达量也随着减少 整个肠道长度的水平，包括结肠。一般来说，缺氧、缺铁 上调铁吸收以及 DMT1 和 FPN1 表达。我们在入住期间感到惊喜 初步研究，当我们发现醛固酮增强 DMT1 和 FPN1 表达，并增加 大鼠结肠中铁的吸收。由于“aldo”会刺激大鼠和大鼠的上皮 Na+ 通道 (ENaC) 人类，我们建议“aldo”还可以通过增强 DMT1 和 FPN1 来刺激铁吸收 在人类结肠中的表达。 “aldo”增强结肠铁吸收的鉴定将作为 刺激十二指肠铁障碍患者铁吸收的替代部位和独特机制 吸收。因此，我们提出以下目标。具体的 Aim-1 将识别并建立铁 正常人结肠的转运蛋白和铁吸收能力。我们将通过以下方式完成这项任务 通过测量上皮中的 59FeSO4 通量来表征铁转运蛋白和跨上皮铁吸收 层和类器官；并且通过建立跨上皮铁吸收需要协调调节 使用 siRNA 转染选择性敲低顶端 (DMT1) 和基底外侧 (FPN1) 转运蛋白。具体的 Aim-2 将致力于确定刺激正常铁转运蛋白和铁吸收的机制。 人类结肠。这将通过确定“aldo”增强铁转运蛋白和反式来实现。 上皮铁吸收并通过识别一种或多种特异性上调的促炎细胞因子 结肠上皮层和结肠样中 DMT1 和 FPN1 的表达以及铁吸收能力。