BELGRADE RAT: A MUTATION IN A CRITICAL METAL TRANSPORTER

贝尔格莱德大鼠：关键金属转运蛋白的突变

• 批准号: 6517946
• 负责人: LAURA M GARRICK
• 金额: $ 30.18万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-03-01 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6517946
• 关键词: cadmium; cobalt; copper; disease /disorder model; divalent metal; gastrointestinal absorption /transport; gene mutation; hereditary hemochromatosis; homeostasis; ion transport; iron metabolism; iron storage disorder; laboratory rat; lead; major histocompatibility complex; manganese; membrane transport proteins; messenger RNA; metal metabolism; metals; microcytic /hypochromic anemia; mutant; nickel; tissue /cell culture; zinc

DESCRIPTION (Adapted from the applicant's abstract): The Belgrade (b/b) rat has a G185R mutation in DMT1, resulting in a hypochromic, microcytic anemia that is inherited as a recessive. DMT1 is a Fe2+/H+ symporter, transporting iron into the duodenum and out of the erythroid endosome. In an expression assay in ooctyes, DMT1 also appears to transport other divalent metals. This proposal is designed to preserve and make available a valuable animal model that is at risk of disappearing just after its mutational basis has been identified. One aim of the proposed research is to understand the role of DMT1 in iron flux and homeostasis and its role in the flux and homeostasis of other metals. The applicants plan to determine metal uptake activity of wild type (185G) and mutant (185R) constructs in a HEK293T cell assay to learn if the mutation affects uptake of each of eight metals (Fe, Mn, Co, Ni, Zn, Cu, Cd and Pb). The applicants will also measure tissue levels of these eight metals in +/+, +/b and b/b rats to see if the levels correlate with mutations in the DMT1 gene itself. A second aim is to learn the role of two isoforms of DMT1 mRNA encoding isoforms of DMT1 that differ in their C-terminal regions. The mutant also provides an opportunity to begin to understand how iron flux and the flux of other metals can continue sufficient for survival of the rat with DMT1 function "knocked out." These aims will also be evaluated relative to systemic iron status, and in other mutants affecting the HFE gene and beta2-microglobulin, a protein complex recently shown to play a regulatory role in iron uptake. The proposed research should have a significant bearing on understanding the basis of iron deficiency, the most prevalent disorder in the world; on iron overload including hereditary hemochromatosis, the most prevalent genetic disease in the US; and on nutrition and toxicity of the other seven metals, of which several, including lead and manganese, have important public health relevance.

描述（改编自申请人的摘要）：贝尔格莱德（b/b）老鼠 在DMT1中具有G185R突变，导致低色素，微细胞贫血 这是继承的隐性。 DMT1是Fe2+/H+ Symporter，运输 熨烫进入十二指肠并从红细胞内部体内熨烫。 在表达中 在Ooctyes中的测定，DMT1似乎也可以运输其他二价金属。 这 建议旨在保存和提供有价值的动物模型 在其突变基础之后消失的风险是 确定。 拟议研究的目的之一是了解 DMT1在铁通量和体内平衡中及其在磁通和稳态中的作用 其他金属。 申请人计划确定野生的金属吸收活性 HEK293T细胞测定中的类型（185G）和突变体（185R）构建 突变会影响八种金属中的每一种（Fe，Mn，Co，Ni，Zn，Cu，Cu， CD和PB）。 申请人还将测量这八个的组织水平 +/ +， +/b和b/b大鼠中的金属查看水平是否与突变相关 在DMT1基因本身中。 第二个目的是学习两个同工型的作用 DMT1 MRNA编码在C末端区域不同的DMT1的同工型。 该突变体还提供了一个机会开始了解铁通量 而且其他金属的通量可以持续到足以生存的大鼠 使用DMT1函数“被淘汰”。 这些目标也将相对评估 达到系统性铁的状态，以及其他影响HFE基因的突变体 Beta2-Microglobolin，最近显示的蛋白质复合物 在铁吸收中的作用。 拟议的研究应该具有重要的影响 了解铁缺乏症的基础，是最普遍的疾病 世界；铁超负荷包括遗传性血色素症，最多 美国流行的遗传疾病；以及关于营养和毒性的 其他七种金属，其中几种，包括铅和锰， 重要的公共卫生相关性。