Structural Basis of Multidrug resistance in Cancer

癌症多药耐药性的结构基础

• 批准号: 7343402
• 负责人: OLUWATOYIN Ajibola ASOJO
• 金额: $ 3.28万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-03 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7343402
• 关键词: ABCG2 gene; ATP phosphohydrolase; ATP-Binding Cassette Transporters; Accounting; Amino Acids; Arginine; Binding; Biological Assay; Breast; Cells; Colon; Complex; Data; Development; Drug Transport; Drug resistance; Environment; Family; Fibroblasts; Genes; Genus Cola; Glycine; Glycoproteins; Goals; Human; In Vitro; Institutes; Length; Lung; Malignant Neoplasms; Measures; Membrane; Membrane Transport Proteins; Mentored Research Scientist Development Award; Mentors; Mitoxantrone; Multi-Drug Resistance; Multiple Myeloma; N-terminal; Normal Cell; Nucleotides; Ovarian Carcinoma; Ovary; Pharmaceutical Preparations; Phase; Placenta; Play; Point Mutation; Positioning Attribute; Property; Proteins; Relapse; Research Proposals; Resistance; Roentgen Rays; Role; Sequence Homology; Series; Structure; Testing; Therapeutic; Threonine; Time; anticancer research; base; cancer cell; chemotherapy; cytotoxicity; fibrosarcoma; human ABCG2 protein; in vivo; inhibitor/antagonist; member; mutant; novel; skills; success; three dimensional structure

Multidrug resistance is a major obstacle to curing cancer because cancer cells become resistant to diverse and unrelated therapeutic compounds. A mechanism for multidrug resistance is the active extrusion of chemotherapeutic drugs from cancer cells by ABC transporters. ABCG2 is a promiscuous ABC transporter of many unrelated compounds. Mutant forms of ABCG2 are expressed in elevated levels in multidrug resistant cancers of diverse origins including fibroblasts, breast, colon, lung, and ovaries. The mechanisms of drug transport remain unclear and the functions of each domain of ABCG2 are neither tested nor confirmed. Furthermore, there are no 3-dimensional structures of ABCG2. The following specific aims are proposed to rectify this situation: 1) To characterize full length ABCG2 and its domains. The activity of each domain of ABCG2 will be tested using assays that measure cytotoxicity, ATPase activity, drug binding and drug extrusion. 2) To determine 3-dimensional structures of ABCG2's cytosolic domain. X-ray structures will be solved that reveal the mode of binding of nucleotides to the cytosolic domain. 3) To determine 3-dimensional structures of full length ABCG2 and domains. Structures will be solved of full length and active domains of ABCG2. The correlation of structural and activity data will clarify the mechanism of drug transport by ABCG2 and homologous transporters, thus spearheading new strategies for the development of novel chemotherapies for multidrug resistant cancer. Specific aims 1 and 2 are proposed for Phase I, while specific aim 3 is proposed for Phase II of the K01 award and beyond. The K01 will afford the applicant protected time to develop new skills and to apply existing skills to cancer research, with the guidance of her mentors, at the stimulating educational environment of the Eppley Institute. She will then be ready to successfully compete for and obtain an independent tenure track position in cancer research.

多药耐药性是治愈癌症的主要障碍，因为癌细胞对多种 和无关的治疗化合物。多药电阻的机制是主动挤压 ABC转运蛋白来自癌细胞的化学治疗药物。 ABCG2是一个混杂的ABC转运蛋白 在许多无关的化合物中。 ABCG2的突变形式在多饮中以较高的水平表达 多种起源的抗性癌症，包括成纤维细胞，乳腺，结肠，肺和卵巢。机制 药物运输的运输仍然不清楚，ABCG2每个域的功能既没有测试，也不 确认的。此外，没有ABCG2的三维结构。以下具体目的是 提议纠正这种情况：1）表征全长ABCG2及其域。活动 ABCG2的每个结构域将使用测量细胞毒性，ATPase活性，药物结合的测定 和药物挤出。 2）确定ABCG2胞质结构域的3维结构。 X射线 将解决结构，以揭示核苷酸与胞质结构域结合的方式。 3）到 确定全长ABCG2和域的3维结构。结构将通过完整解决 ABCG2的长度和活动域。结构和活动数据的相关性将阐明 ABCG2和同源转运蛋白的药物传输机制，从而率先采用新策略 用于开发用于多药抗癌的新型化学疗法。具体目标1和2是 提出了第一阶段的建议，而特定的目标3提出了K01奖及以后的第二阶段。 K01 将负担申请人的保护时间来发展新技能并将现有技能应用于癌症研究， 在她的导师的指导下，在Eppley Institute的刺激性教育环境中。她 然后，将准备成功竞争并获得癌症中独立的任期位置 研究。