权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.

项目总结/文摘

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

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

DOI：
10.1002/hep.26401
发表时间：
2013-08
期刊：
Hepatology (Baltimore, Md.)
影响因子：
0
作者：
Wang CY;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