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The biology of gastrin-ferric ion complexes

胃泌素-铁离子复合物的生物学

基本信息

批准号：
7648265
负责人：
GRAHAM S BALDWIN
金额：
$ 15.73万
依托单位：
UNIVERSITY OF MELBOURNE
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-08-01 至 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7648265
关键词：
Affinity Amino Acids Animal Model Animals Binding Biological Biology Bismuth C-terminal Carcinoid Tumor Carcinoma Cell Line Chelating Agents Cholecystokinin B Receptor Clinical Research Collaborations Colon Carcinoma Colorectal Colorectal Cancer Complex Data Defect Development Dietary Iron Disease Effectiveness Excision Funding Gastric Parietal Cells Gastrins Goals Growth Factor Growth and Development function Health Helicobacter pylori Hemochromatosis Homeostasis Hormones Human In Vitro Inpatients Ions Iron Iron Metabolism Disorders Iron Overload Laboratories Large Intestine Carcinoma Lead Length Malignant Epithelial Cell Malignant Neoplasms Maps Measures Metals Modeling Mouse Strains Mucous Membrane Mus Neoplasm Metastasis Pancreas Paper Patients Pattern Peptides Play Principal Investigator Process Property Proteolytic Processing Publishing Recording of previous events Reporting Research Design Research Personnel Risk Role Serum Signal Pathway Staging Stomach Structure Testing Transferrin Transgenic Mice X-Ray Crystallography amidation base cell motility crosslink gastrin inhibitor in vitro activity in vivo inhibitor/antagonist insulin dimers interdisciplinary collaboration mutant novel progastrin programs receptor research study skills trafficking uptake

项目摘要

DESCRIPTION (provided by applicant): The long-term objective of this project is to understand the biological significance of the complex between ferric ions and non-amidated gastrins (NAGs). This laboratory has shown that NAGs selectively bind 2 ferric ions that ferric ion binding is essential for biological activity in vitro, and that gastrin interacts with transferrin. The specific aims of the project are: (1) to determine whether or not ferric ions are essential for the stimulation of colorectal carcinoma (CRC) development by NAGs in vivo, (2) to develop NAG antagonists, (3) to establish the role of NAGs in iron homeostasis, and (4) to define the role of the NAG-transferrin complex in cellular ion uptake and determine its structure. The health significance of the project lies in the facts that NAGs act as growth factors for the normal gastric and colonic mucosa, accelerate the development of both gastric and colorectal cancer, and may be involved in disorders of iron homeostasis. The research design mirrors the specific aims, and utilizes the unique combination of skills of the principal investigators. Firstly, agents known to block the binding of ferric ions to NAGs will be tested as NAG inhibitors in four animal models of CRC development. Secondly, exchange inert metal ion-NAG complexes and structurally modified gastrin fragments will be tested as NAG inhibitors in CRC cell lines and in animal CRC models. Thirdly, patterns of progastrin expression and processing will be measured by radioimmunoassy in mice with altered dietary iron uptake, and in patients with hemochromatosis. Iron status will also be measured in hypergastrinemic and gastrin-deficient transgenic mice with altered dietary iron uptake, and in patients with hypergastrinemia. Fourthly, the role of the gastrin/transferrin complex in cellular iron trafficking will be investigated, and covalent cross-linking and X-ray crystallography with a panel of NAG and transferrin mutants will be used to define the structural requirements for formation of the complex. These studies are expected to demonstrate an unexpected role for ferric ions in gastrin bioactivity in vivo, and for gastrins in ferric ion homeostasis. Recognition that metal ions are essential for the biological activity of NAGs may permit the development of novel therapies for colon cancer.

描述（由申请人提供）：本项目的长期目标是了解三价铁离子和非酰胺化胃泌素（NAG）之间复合物的生物学意义。该实验室已经表明NAG选择性地结合2个铁离子，铁离子结合对于体外生物活性是必需的，并且胃泌素与转铁蛋白相互作用。该项目的具体目标是：（1）确定三价铁离子是否是NAG体内刺激结直肠癌（CRC）发展所必需的，（2）开发NAG拮抗剂，（3）确定NAG在铁稳态中的作用，以及（4）确定NAG-转铁蛋白复合物在细胞离子摄取中的作用并确定其结构。该项目的健康意义在于NAG作为正常胃和结肠粘膜的生长因子，加速胃癌和结直肠癌的发展，并可能参与铁稳态失调。研究设计反映了具体的目标，并利用了主要研究者独特的技能组合。首先，已知阻断三价铁离子与NAG结合的试剂将在CRC发展的四种动物模型中作为NAG抑制剂进行测试。其次，将在CRC细胞系和动物CRC模型中测试交换惰性金属离子-NAG复合物和结构修饰的胃泌素片段作为NAG抑制剂。第三，将通过放射免疫测定法测量饮食铁摄入改变的小鼠和血色素沉着症患者的前胃泌素表达和加工模式。还将在饮食铁摄取改变的高胃泌素血症和胃泌素缺乏转基因小鼠以及高胃泌素血症患者中测量铁状态。第四，将研究胃泌素/转铁蛋白复合物在细胞铁转运中的作用，并使用一组NAG和转铁蛋白突变体的共价交联和X射线晶体学来定义复合物形成的结构要求。预期这些研究将证明铁离子在体内胃泌素生物活性中以及胃泌素在铁离子稳态中的意想不到的作用。认识到金属离子对NAG的生物活性是必不可少的，可能会允许开发用于结肠癌的新疗法。

项目成果

期刊论文数量（26）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Gastrins, iron homeostasis and colorectal cancer.

DOI：
10.1016/j.bbamcr.2011.02.007
发表时间：
2011-05
期刊：
Biochimica et biophysica acta
影响因子：
0
作者：
Kovac S;Anderson GJ;Baldwin GS
通讯作者：
Baldwin GS

Bismuth ions inhibit the biological activity of non-amidated gastrins in vivo.

DOI：
10.1016/j.bcp.2011.11.030
发表时间：
2012-02-15
期刊：
BIOCHEMICAL PHARMACOLOGY
影响因子：
5.8
作者：
Kovac, Suzana;Loh, Su-Wen;Lachal, Shamilah;Shulkes, Arthur;Baldwin, Graham S.
通讯作者：
Baldwin, Graham S.

Expression of gastrin precursors by CD133-positive colorectal cancer cells is crucial for tumour growth.