Role of the Kidney in Iron Balance

肾脏在铁平衡中的作用

基本信息

批准号：
9247896
负责人：
Katherine Xu
金额：
$ 4.4万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9247896
关键词：
ATP phosphohydrolase Acute Acute Renal Failure with Renal Papillary Necrosis Adult Affect Anemia Apical Appearance Back Binding Biological Availability Biology Blood Blood Circulation Bone Marrow Bowman&apos s space Brain Hypoxia-Ischemia Bypass Cell membrane Cells Chelating Agents Chemistry Chronic Complex Data Development Distal Duct (organ) structure Duodenum Energy Metabolism Enterocytes Environment Equilibrium Erythroblasts Failure Food Genes Genetic Hand Hemochromatosis Hepatocyte Hormones Host Defense Human Impairment Injury Iron Iron Chelating Agents Iron Overload Kidney Knock-out LCN2 gene LDL-Receptor Related Protein 2 Limb structure Liver Location LoxP-flanked allele Lysosomes Maps Mediating Membrane Micronutrients Modeling Molecular Mus Nephrons Oxidants Oxygen Pathway interactions Pattern Pharmacology Phosphate Buffer Physiology Play Polymers Proteins Public Health Reactive Oxygen Species Recycling Reducing Agents Research Role SLC11A2 gene Series Serum Source TFRC gene Testing Thick TimeLine Tissues Tracer Transferrin Tubular formation Urine Vesicle Water Woman cell injury cell type chelation hepcidin inorganic phosphate intrinsic factor-cobalamin receptor iron deficiency macrophage metal transporting protein 1 mutant novel nucleotide metabolism nutrition organ growth oxidation oxygen transport protein transport public health relevance symporter tool trafficking urinary

项目摘要

DESCRIPTION (provided by applicant): The biology of iron transport is dictated by the chemistry of iron. Free iron is present around 10-10M in water at neutral pH (in an oxygenated solution) and around 10-19M in the presence of phosphate buffers, concentrations too low to support cellular viability. Consequently, from the moment iron is liberated from food sources, to its final distribution in the cell, iron must be "handed-off" from one chelator to another chelator Failure of chelation, which is tantamount to the presentation of iron to reducing or oxidizing agents, results in reactive chemistry, while appropriate chelation solubilizes and protects iron from changes in oxidation state. In the past decade, a series of iron chelators, carriers and transporters (both proteins and organic molecules) have been identified which affect the exchange of iron from the gut lumen to nearly every cell of the body, even at neutral pH, in the presence of oxygen. These proteins and organic molecules provide both short range transport (across cell membranes) and long range transport (through the circulation) to deliver adequate amounts of iron to target cells and recycle iron from damaged cells. Almost no iron is lost to the environment meaning that the steady state can be maintained with limited replacement (approximately 1mg per day in humans). This means the capture and trafficking pathways are efficient and export of iron to the environment is contained. Mechanisms that capture and recycle iron have been described and have been most importantly studied in duodenal enterocytes or macrophages. Yet, a number of proteins which carry iron are filtered into the nephron, and acute and chronic kidney injury is well known to result in the appearance of iron in the urine, resulting in catalytic iron mediated damage. To understand iron trafficking in the kidney requires an analysis of iron trafficking proteins in many cell types along the course of the nephron. I have identified both canonical and non-cannonical localizations of these proteins in the nephron and I propose to understand how they remove iron from the urinary space and transport it safely to the blood. My lab has the expertise and all of the standard tools required fr these studies, such as a series of floxed-iron transporter genes, novel Cre Drivers, and tracers loaded with iron, to detect the location of cellular and urinary iron when different transporters ae deleted. Our preliminary results suggest that both proximal and distal nephron mechanisms are at play to capture iron including entirely unexpected mechanisms of luminal iron traffic. The preliminary results also suggest that renal iron traffic may be under control of hepcidin, meaning that like the liver, duodenum, and macrophage, the kidney is engaged not only in local iron trafficking but is likely to be a contributor to systemic iron balance. Results from the proposed study will provide molecular implications for iron-mediated damage in acute kidney injury.

描述（由申请人提供）：铁转运的生物学特性由铁的化学性质决定。在中性 pH 值的水中（含氧溶液），游离铁的含量约为 10-10M，在磷酸盐缓冲液存在的情况下，游离铁的含量约为 10-19M。，浓度太低，无法支持细胞活力，从铁从食物来源释放到细胞中的最终分布，铁必须从一种螯合剂“传递”到另一种螯合剂失败。螯合作用相当于将铁呈现给还原剂或氧化剂，从而产生反应性化学反应，同时适当的螯合可以溶解铁并防止其氧化态发生变化。在过去的十年中，出现了一系列铁螯合剂、载体和转运蛋白。已发现，即使在中性 pH 值和有氧存在的情况下，铁从肠腔到身体几乎每个细胞的交换也会受到影响。短程运输（跨细胞膜）和长程运输（通过循环）将足够量的铁输送到目标细胞并从受损细胞中回收铁，几乎没有铁流失到环境中，这意味着可以维持稳定状态。有限的替代（人类每天大约 1 毫克），这意味着捕获和运输途径是有效的，并且捕获和回收铁的机制已被描述，并且已在十二指肠肠细胞或中进行了最重要的研究。然而，许多携带铁的蛋白质被过滤到肾单位，众所周知，急性和慢性肾损伤会导致尿液中出现铁，从而导致铁介导的催化损伤。肾脏需要对许多细胞类型中的铁运输蛋白进行分析我已经确定了这些蛋白质在肾单位中的典型和非典型定位，并且我建议了解它们如何从泌尿道空间中去除铁并将其安全地输送到血液中。这些研究需要，例如一系列的floxed铁转运蛋白基因、新型Cre驱动器和负载铁的示踪剂，以检测当不同转运蛋白被删除时细胞和尿液中铁的位置。我们的初步结果表明，近端和远端肾单位机制都在捕获铁，包括完全意想不到的管腔铁运输机制。初步结果还表明，肾铁运输可能受到铁调素的控制，这意味着像肝脏、十二指肠一样。和巨噬细胞，肾脏不仅参与局部铁运输，而且可能促进全身铁平衡，该研究的结果将为急性肾损伤中铁介导的损伤提供分子意义。