The biology of gastrin-ferric ion complexes

胃泌素-铁离子复合物的生物学

• 批准号: 7033598
• 负责人: GRAHAM S BALDWIN
• 金额: $ 16.2万
• 依托单位: UNIVERSITY OF MELBOURNE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7033598
• 关键词: amidation /deamidation; binding sites; calcium ion; cell adhesion; cell line; cell migration; cell proliferation; chemical structure function; cofactor; electron spin resonance spectroscopy; gastric mucosa; gastrins; glycine; hormone receptor; hormone regulation /control mechanism; intestinal mucosa; iron compounds; laboratory mouse; laboratory rabbit; laboratory rat; metal complex; nuclear magnetic resonance spectroscopy; peptide hormone biosynthesis; receptor binding; synthetic peptide; tissue /cell culture

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）：该项目的长期目的是了解铁离子和非酰胺胃（NAGS）之间复合物的生物学意义。该实验室表明，NAG选择性地结合了2个铁离子，即铁离子结合对于体外生物学活性至关重要，并且胃蛋白与转铁蛋白相互作用。 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.该项目的健康意义在于，NAG是正常胃和结肠粘膜的生长因子，加速了胃癌和结直肠癌的发展，并且可能与铁稳态疾病有关。研究设计反映了特定的目的，并利用了主要研究人员的独特技能组合。首先，在CRC发育的四种动物模型中，已知可以阻止铁离子与NAG结合的试剂将作为NAG抑制剂进行测试。其次，交换惰性金属离子-NAG复合物和结构修饰的胃片片段将在CRC细胞系和动物CRC模型中作为NAG抑制剂进行测试。第三，在饮食中铁的摄取改变的小鼠和血色素沉着症患者中，将通过放射免疫和加工的模式来测量。铁状态还将在饮食中摄取改变的高胃血症和胃蛋白缺陷的转基因小鼠和高胃血症患者中测量。第四，将研究胃蛋白/转铁蛋白复合物在细胞铁运输中的作用，并将使用一组NAG和转铁蛋白突变体的共价交联和X射线晶体学来定义形成络合物的结构要求。预计这些研究将证明铁离子在体内胃蛋白生物活性和铁离子体内稳态中的意外作用。认识到金属离子对于NAG的生物学活性至关重要，可以开发出新的结肠癌疗法。