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.

项目摘要/摘要铁超负荷遗传性血色素沉着症是一种内分泌肝病，是由于无法为了产生足够量的肝素，肝脏产生的铁调节激素。在血色素肿瘤病，饮食中铁的吸收增加导致血浆非转移蛋白结合的出现铁（NTBI），由各种组织和细胞吸收，导致组织铁超载和相关病理。血浆NTBI也通常在血液学疾病thalassyapia大专业中看到，这是一种遗传性血液疾病这需要定期输血，随着时间的流逝，这会导致铁超负荷。虽然NTBI是主要的导致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。该提议的主要长期目标是定义将铁运输到的蛋白质各种组织和细胞，尤其是受铁超载相关病理影响的组织和细胞。我们的中心假设是膜转运蛋白Zip14和Zip8参与铁稳态和NTBI摄取。在以前的资金期我们发现Zip14是肝细胞中的主要NTBI摄取机制胰腺腺泡细胞，Zip14是在小鼠模型中肝和胰腺铁负载所必需的血色素沉着和饮食中的铁超负荷。我们还产生了各种有条件的Zip8敲除鼠标询问Zip8在铁代谢和铁超载中的作用的模型。在拟议研究的目标1中，我们将继续使用Zip14敲除（Zip14 - / - ）小鼠来定义Zip14在组织铁载荷中的作用与血压敲除（HJV - / - ）小鼠相互交叉，这是一种少年血色素沉着病的模型。当前的重点将使用内分泌器官，包括垂体前腺和肾上腺。使用HJV - / - 鼠标，我们将还可以评估降低Zip14表达（药理学或遗传上）与铁结合的疗效缓解组织铁超负荷的螯合。在AIM 2中，我们将确定Zip14介导的铁负荷胰腺β细胞会导致β细胞功能障碍和糖尿病。为此，我们生成了一个转基因鼠标模拟过表达在β细胞中专门表达Zip14的模型。当用铁加载时，Zip14转基因小鼠，与负载的人类类似，在β细胞中积聚铁并发展糖尿病。我们将表征这些小鼠中糖尿病的发展，重点是β细胞中发生的变化。在AIM 3中，我们将继续为了定义Zip8在铁稳态中的作用，尤其是其在压力红细胞生成中的明显作用。定义 Zip8在组织铁载荷中的作用，我们将利用可诱导的zip8 - / - 小鼠以及zip8 - / - ; zip14 - / - double 敲除小鼠，这将有助于确定这两种同源蛋白是否可以补偿每种其他。

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）

Impaired iron status in aging research.

DOI：
10.3390/ijms13022368
发表时间：
2012
期刊：
International journal of molecular sciences
影响因子：
5.6
作者：
Xu J;Jia Z;Knutson MD;Leeuwenburgh C
通讯作者：
Leeuwenburgh C

Iron and manganese transport in mammalian systems.

DOI：
10.1016/j.bbamcr.2020.118890
发表时间：
2021-01
期刊：
Biochimica et biophysica acta. Molecular cell research
影响因子：
0
作者：
Liu Q;Barker S;Knutson MD
通讯作者：
Knutson MD

Measurement of Transferrin- and Non-transferrin-bound Iron Uptake by Mouse Tissues.

小鼠组织对转铁蛋白和非转铁蛋白结合铁摄取的测量。

DOI：
10.21769/bioprotoc.1922
发表时间：
2016
期刊：
Bio-protocol
影响因子：
0.8
作者：
Jenkitkasemwong,Supak;Wang,Chia-Yu;Knutson,MitchellD
通讯作者：
Knutson,MitchellD

Long-term perturbation of muscle iron homeostasis following hindlimb suspension in old rats is associated with high levels of oxidative stress and impaired recovery from atrophy.

老年大鼠后肢悬吊后肌肉铁稳态的长期扰动与高水平的氧化应激和萎缩恢复受损有关。

DOI：
10.1016/j.exger.2011.10.011
发表时间：
2012
期刊：
Experimental gerontology
影响因子：
3.9
作者：
Xu,Jinze;Hwang,JudyCY;Lees,HazelA;Wohlgemuth,StephanieE;Knutson,MitchellD;Judge,AndrewR;Dupont-Versteegden,EstherE;Marzetti,Emanuele;Leeuwenburgh,Christiaan
通讯作者：
Leeuwenburgh,Christiaan

Hepatocyte divalent metal-ion transporter-1 is dispensable for hepatic iron accumulation and non-transferrin-bound iron uptake in mice.