Targeting the amino terminal gate of human MRP1

靶向人类 MRP1 的氨基末端门

• 批准号: 7628677
• 负责人: Jian-Ting Zhang
• 金额: $ 28.79万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7628677
• 关键词: ABCB1 gene; ATP-Binding Cassette Transporters; Antibodies; Antineoplastic Agents; Binding; Biochemical; Cancer Patient; Cell membrane; Cells; Cytoplasm; Dimerization; Drug Efflux; Drug Transport; Drug resistance; Electron Microscopy; Engineering; Environment; Epitopes; Goals; Human; Image; Indiana; Label; Laboratories; Lead; Light; Link; Location; Malignant Neoplasms; Maps; Mediating; Membrane; Membrane Proteins; Membrane Transport Proteins; Methods; Mitoxantrone; Molecular; Monoclonal Antibodies; Multi-Drug Resistance; Multidrug Resistance Associated Protein 1; Mutagenesis; Mutate; P-Glycoprotein; P-Glycoproteins; Peptide Phage Display Library; Peptides; Pharmaceutical Preparations; Phase; Proteins; Research Institute; Research Personnel; Resistance; Role; Scanning; Screening procedure; Sequence Alignment; Structure; Testing; Therapeutic Agents; Universities; Work; anticancer research; aqueous; cancer cell; chemotherapy; clinically relevant; dimer; extracellular; human ABCG2 protein; inhibitor/antagonist; novel; programs; success; synthetic peptide

DESCRIPTION (provided by applicant): Multidrug resistance (MDR) is a major problem for successful chemotherapy of human cancers. One of the known mechanisms of MDR in cancer cells is the elevated expression of membrane proteins that mediate efflux of anticancer drugs. Three major membrane proteins that have this drug-efflux function have been identified: P-glycoprotein (Pgp), multidrug resistance-associated protein 1 (MRP1), and breast cancer resistance protein/mitoxantrone resistance protein (BCRP/MXR). These proteins belong to the ATP-binding cassette (ABC) membrane transporter superfamily. The long-term goal of our laboratory is to understand the molecular mechanisms of and to overcome ABC transporter-mediated MDR in cancer cells. Unlike most other ABC-transporters such as Pgp, human MRP1 has an additional membrane-spanning domain (MSD1) with a postulated extracellular amino terminus. However, our recent studies suggested that the amino terminus may be located in cytoplasm and is functionally important. In the next five years of support, we plan to test the hypothesis that the amino terminus of human MRP1 functions as a gating mechanism for drug transport and can be used as a target to inhibit MRP1 activity and to circumvent MRP1-mediated MDR. To this end, we plan to accomplish the following five specific aims: (1) to delineate the membrane orientation of the amino terminus of human MRP1; (2) to investigate the gating role of the amino terminus in drug transport function of human MRP1; (3) to determine the dimeric status and to map the dimerization domain of human MRP1; (4) to develop an inhibitor of human MRP1 from a synthetic peptide with a sequence of the amino terminus of human MRP1; and (5) to develop peptide probes of human MRP1 using synthetic peptides interacting with MSD1 of human MRP1 to investigate the functional mechanism of MRP1. The excellent scientific environment at Indiana University Cancer Research Institute and the generous institutional support will contribute enormously to the likelihood of success of this project. The information and probes obtained from this study will help us understand the molecular mechanism of human MRP1-mediated drug transport. This work may also lead us to the discovery of a new class of therapeutic agents that can help overcome drug-resistant cancers.

描述（由申请人提供）：多药耐药（MDR）是人类癌症成功化疗的主要问题。癌细胞中MDR的已知机制之一是介导抗癌药物外排的膜蛋白的表达升高。具有这种药物外排功能的三种主要膜蛋白已被鉴定：P-糖蛋白（Pgp）、多药耐药相关蛋白1（MRP 1）和乳腺癌耐药蛋白/米托蒽醌耐药蛋白（BCRP/MXR）。这些蛋白属于ATP结合盒（ABC）膜转运蛋白超家族。我们实验室的长期目标是了解ABC转运蛋白介导的肿瘤细胞MDR的分子机制，并克服这种机制。与大多数其他ABC转运蛋白（如Pgp）不同，人MRP 1具有额外的跨膜结构域（MSD 1），并具有假定的细胞外氨基末端。然而，我们最近的研究表明，氨基端可能位于细胞质中，并且在功能上很重要。在未来五年的支持，我们计划测试的假设，即人MRP 1的氨基末端作为门控机制的药物转运，并可以作为一个目标，以抑制MRP 1的活性和规避MRP 1介导的MDR。为此，我们计划完成以下五个具体目标：（1）描绘人MRP 1氨基端的膜取向;（2）研究氨基端在人MRP 1药物转运功能中的门控作用;（3）确定人MRP 1的二聚体状态并绘制二聚体结构域;（4）确定人MRP 1的二聚体结构域。（4）从具有人MRP 1氨基端序列的合成肽开发人MRP 1的抑制剂;（5）利用与人MRP 1的MSD 1相互作用的合成肽开发人MRP 1的肽探针，以研究MRP 1的功能机制。印第安纳州大学癌症研究所的良好科学环境和慷慨的机构支持将极大地促进该项目成功的可能性。本研究所获得的信息和探针将有助于我们了解人MRP 1介导的药物转运的分子机制。这项工作也可能导致我们发现一类新的治疗药物，可以帮助克服耐药性癌症。