Role of the Kidney in Iron Balance

肾脏在铁平衡中的作用

基本信息

批准号：
8910146
负责人：
Katherine Xu
金额：
$ 4.26万
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/8910146
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 Injury Iron Iron Overload Kidney Knock-out Kupffer Cells LDL-Receptor Related Protein 2 Learning Limb structure Liver Location Lysosomes Maps Mediating Membrane Micronutrients Modeling Molecular Mus Nephrons Oxidants Oxygen Pathway interactions Pattern Phosphate Buffer Physiology Play Polymers Proteins Public Health Reactive Oxygen Species Recycling Reducing Agents Research Role SLC11A2 gene Series Serum Solutions Source Testing Thick TimeLine Tissues Tracer Transferrin Tubular formation Urine Vesicle Water Woman cell injury cell type chelation hepcidin human TFRC protein inorganic phosphate intrinsic factor-cobalamin receptor iron deficiency macrophage metal transporting protein 1 mutant neuronal cell body 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（由适用提供）：铁运输的生物学由铁的化学决定。在中性pH值（在氧化溶液中）和在存在磷酸盐缓冲液的存在下，在水中存在自由铁，在水中（在氧化溶液中）约为10-19m，浓度太低而无法支持细胞活力。因此，从食物来源释放到在细胞中的最终分布中，必须将铁从一个螯合剂到另一个螯合剂的螯合剂“交接”，这是静脉固化的，这涉及将铁的呈现到还原或氧化剂，从而导致反应性化学，同时适当的螯合溶解和保护铁免受氧化状态变化的铁。在过去的十年中，已经鉴定出一系列铁螯合剂，载体和转运蛋白（蛋白质和有机分子）在存在氧气的情况下影响了铁从肠腔到几乎每个细胞，即使在中性pH下的每个细胞的交换。这些蛋白质和有机分子提供短距离传输（通过循环）（通过循环）提供短范围的转运（通过循环），以将铁量足以向靶细胞提供足够的铁和从受损细胞中回收铁。几乎没有铁在环境中丢失，这意味着稳态可以保持有限的替换（人类每天约1mg）。这意味着捕获和贩运途径是有效的，并将铁出口到环境中。已经描述了捕获和回收铁的机制，并且在十二指肠肠细胞或巨噬细胞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中，众所周知，急性和慢性肾损伤会导致尿液中的铁出现，从而导致催化铁介导的损伤。要了解肾脏中的铁运输需要对许多细胞类型的铁运输蛋白进行分析肾单位。我已经确定了这些蛋白质中这些蛋白质中的规范和非通道的局部定位，并建议了解它们如何从尿液空间中去除铁并安全地将其安全地运送到血液中。我的实验室具有这些研究所需的专业知识和所有标准工具，例如一系列floxed-rox-rox-rox-rox-roxed-roxed-roxed-rocked-rocked-rocked transporter基因，新颖的CRE驱动器和装有铁的示踪剂，以检测当删除不同转运蛋白时细胞和尿铁的位置。我们的初步结果表明，近端和不同的肾单位机制都在起作用，以捕获铁，包括完全出乎意料的腔内铁交通机制。初步结果还表明，肾铁的流量可能受到肝素的控制，这意味着像肝脏，十二指肠和巨噬细胞一样，肾脏不仅参与了当地的铁贩运，而且很可能是系统性铁平衡的贡献者。拟议的研究的结果将为铁介导的急性肾损伤造成的损伤提供分子意义。