Zip Proteins and Iron Metabolism

Zip 蛋白质和铁代谢

基本信息

批准号：
10396019
负责人：
Mitchell D Knutson
金额：
$ 37.17万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-17 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10396019
关键词：
Acinar Cell Adolescent Adrenal Glands Adult Affect Age-Months Animal Model Anterior Pituitary Gland Appearance Beta Cell Blood Transfusion Cardiac Myocytes Cardiomyopathies Cause of Death Cell physiology Cells Clinical Complication Cooley&apos s anemia Data Development Diabetes Mellitus Dietary Iron Disease Endocrine Endocrine Glands Erythropoiesis Family member Functional disorder Funding Genes Glucose Goals Grant HFE2 gene Heart Hematological Disease Hemochromatosis Hepatocyte Hereditary Disease Hereditary hemochromatosis Homeostasis Homologous Protein Hormones Human Inherited Ions Iron Iron Chelation Iron Overload Klinefelter&apos s Syndrome Knock-out Knockout Mice Knowledge Lead Liver Liver diseases Mediating Membrane Proteins Membrane Transport Proteins Modeling Molecular Mus Organ Oxidation-Reduction Pancreas Pathology Pathway interactions Patients Pharmacology Phenotype Pituitary Gland Placenta Plasma Proteins Rattus Research Resistance Risk Rodent Role Stress Structure of beta Cell of islet Time Tissues Transgenic Mice ZIP protein Zinc absorption defined contribution diabetes risk diabetic divalent metal hepcidin in vivo insight iron metabolism islet mouse model overexpression prevent protein metabolism protein transport therapeutic candidate therapeutic target transcriptome sequencing uptake

项目摘要

PROJECT SUMMARY/ABSTRACT The iron overload disorder hereditary hemochromatosis is an endocrine liver disease that results from an inability to produce sufficient amounts of hepcidin, the iron-regulatory hormone produced by the liver. In hemochromatosis, increased absorption of dietary iron leads to the appearance of plasma non-transferrin-bound iron (NTBI), which is taken up by various tissues and cells leading to tissue iron overload and related pathology. Plasma NTBI is also commonly seen in the hematologic disease thalassemia major, an inherited blood disorder that requires regular blood transfusions, which over time result in iron overload. Although NTBI is the major contributor to tissue iron loading, our understanding of the molecular mechanisms that mediate NTBI uptake is incomplete. The primary long-term objective of this proposal is to define the proteins that transport iron into various tissues and cells, particularly those affected by iron-overload related pathology. Our central hypothesis is that the membrane transport proteins ZIP14 and ZIP8 participate in iron homeostasis and NTBI uptake. In the previous funding period we found that ZIP14 is the primary NTBI uptake mechanism in hepatocytes and pancreatic acinar cells, and that ZIP14 is required for iron loading of the liver and pancreas in mouse models of hemochromatosis and dietary iron overload. We also generated a variety of conditional Zip8 knockout mouse models to interrogate the roles of ZIP8 in iron metabolism and iron overload. In Aim 1 of the proposed research, we will continue to define the roles of ZIP14 in tissue iron loading by using ZIP14 knockout (Zip14-/-) mice intercrossed with hemojuvelin knockout (Hjv-/-) mice, a model of juvenile hemochromatosis. The current focus will be on endocrine organs including the anterior pituitary gland and adrenal gland. Using Hjv-/- mice, we will also assess the efficacy of reducing ZIP14 expression (pharmacologically or genetically) combined with iron chelation in mitigating tissue iron overload. In Aim 2, we will determine how ZIP14-mediated iron loading of pancreatic beta cells leads to beta cell dysfunction and diabetes. For this aim we generated a transgenic mouse model that overexpresses ZIP14 specifically in beta cells. When loaded with iron, the ZIP14 transgenic mice, similar to iron-loaded humans, accumulate iron in beta cells and develop diabetes. We will characterize the development of diabetes in these mice, focusing on changes that occur in beta cells. In Aim 3, we will continue to define the roles of ZIP8 in iron homeostasis, particularly its apparent role in stress erythropoiesis. To define the roles of ZIP8 in tissue iron loading, we will utilize inducible Zip8-/- mice as well as Zip8-/-;Zip14-/- double knockout mice, which will help to determine whether these two homologous proteins can compensate for each other.

项目概要/摘要铁超载症遗传性血色素沉着症是一种内分泌性肝病，是由于无法产生足够量的铁调素（肝脏产生的铁调节激素）。在血色素沉着症，膳食铁吸收增加导致血浆非转铁蛋白结合的出现铁（NTBI），被各种组织和细胞吸收，导致组织铁超载和相关病理。血浆 NTBI 也常见于重型地中海贫血（一种遗传性血液疾病）的血液系统疾病这需要定期输血，随着时间的推移会导致铁过载。虽然 NTBI 是主要的组织铁负荷的贡献者，我们对介导 NTBI 摄取的分子机制的理解是不完整。该提案的主要长期目标是确定将铁转运到体内的蛋白质各种组织和细胞，特别是那些受铁超载相关病理影响的组织和细胞。我们的中心假设膜转运蛋白 ZIP14 和 ZIP8 参与铁稳态和 NTBI 摄取。在在之前的资助期间，我们发现 ZIP14 是肝细胞中主要的 NTBI 摄取机制，并且胰腺腺泡细胞，并且 ZIP14 是小鼠模型中肝脏和胰腺铁负荷所必需的血色素沉着症和膳食铁超载。我们还生成了多种条件性Zip8基因敲除小鼠探究 ZIP8 在铁代谢和铁过载中的作用的模型。在拟议研究的目标 1 中，我们将通过使用 ZIP14 敲除 (Zip14-/-) 小鼠继续确定 ZIP14 在组织铁负荷中的作用与血幼蛋白敲除（Hjv-/-）小鼠（一种幼年血色素沉着症模型）杂交。目前的焦点会影响内分泌器官，包括垂体前叶和肾上腺。使用 Hjv-/- 小鼠，我们将还评估降低 ZIP14 表达（药理学或遗传学）与铁结合的功效螯合减轻组织铁过载。在目标 2 中，我们将确定 ZIP14 介导的铁负载如何胰腺β细胞导致β细胞功能障碍和糖尿病。为此，我们培育了一只转基因小鼠 ZIP14 特异地在 β 细胞中过表达的模型。当装载铁时，ZIP14 转基因小鼠，与富含铁的人类类似，铁在β细胞中积累并发展为糖尿病。我们将表征这些小鼠的糖尿病发展，重点关注β细胞中发生的变化。在目标3中，我们将继续定义 ZIP8 在铁稳态中的作用，特别是其在应激性红细胞生成中的明显作用。定义为了了解 ZIP8 在组织铁负荷中的作用，我们将利用诱导型 Zip8-/- 小鼠以及 Zip8-/-;Zip14-/- 双基因敲除小鼠，这将有助于确定这两种同源蛋白是否可以相互补偿其他。

项目成果

期刊论文数量（23）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

ZIP14 and DMT1 in the liver, pancreas, and heart are differentially regulated by iron deficiency and overload: implications for tissue iron uptake in iron-related disorders.

肝脏、胰腺和心脏中的 ZIP14 和 DMT1 受到铁缺乏和过载的差异调节：对铁相关疾病中组织铁吸收的影响。

DOI：
发表时间：
2013-07
期刊：
影响因子：
10.1
作者：
Nam, Hyeyoung;Wang, Chia;Zhang, Lin;Zhang, Wei;Hojyo, Shintaro;Fukada, Toshiyuki;Knutson, Mitchell D
通讯作者：
Knutson, Mitchell D

Correction for “ SLC 39 A 14 deficiency alters manganese homeostasis and excretion resulting in brain manganese accumulation and motor deficits in mice

纠正∀SLC 39 A 14 缺陷会改变锰稳态和排泄，导致小鼠脑部锰积累和运动缺陷

DOI：
发表时间：
2024-09-14
期刊：
影响因子：
0
作者：
Adenike Akinyodea;Elizabeth Paulusa;Ralf Weiskirchenb;Shintaro Hojyoc;Toshiyuki Fukadad;Genesys Giraldog;Jessica Schrierg;Armin Garciag;Christopher Janusg;Benoit Giassong;Mitchell D. Knutsona
通讯作者：
Mitchell D. Knutsona

Non-transferrin-bound iron transporters.

非转铁蛋白结合的铁转运蛋白。