Structural Basis of Multidrug resistance in Cancer

癌症多药耐药性的结构基础

基本信息

批准号：
7625127
负责人：
OLUWATOYIN Ajibola ASOJO
金额：
$ 15.54万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-06-03 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7625127
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 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

项目摘要

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：多药耐药性是治愈癌症的主要障碍，因为癌细胞对多种且不相关的治疗化合物产生耐药性。多药耐药的机制是 ABC 转运蛋白主动将化疗药物从癌细胞中挤出。 ABCG2 是许多不相关化合物的混杂 ABC 转运蛋白。 ABCG2 的突变形式在不同来源的多重耐药癌症中表达水平升高，包括成纤维细胞、乳腺癌、结肠癌、肺癌和卵巢癌。药物转运机制尚不清楚，ABCG2 各结构域的功能也未经过测试或证实。此外，ABCG2 不存在 3 维结构。为了纠正这种情况，提出了以下具体目标： 1) 表征全长 ABCG2 及其域。 ABCG2 每个结构域的活性将使用测量细胞毒性、ATP 酶活性、药物结合和药物挤出的测定法进行测试。 2) 确定ABCG2胞质结构域的3维结构。 X 射线结构将被解析，揭示核苷酸与胞质结构域的结合模式。 3) 确定全长ABCG2和域的3维结构。将解析 ABCG2 的全长和活性域的结构。结构和活性数据的相关性将阐明 ABCG2 和同源转运蛋白的药物转运机制，从而为开发针对多重耐药癌症的新型化疗药物开辟新策略。为第一阶段提出了具体目标 1 和 2，为 K01 奖的第二阶段及以后提出了具体目标 3。 K01 将为申请人提供受保护的时间，以在埃普利研究所的刺激性教育环境中，在导师的指导下，发展新技能并将现有技能应用于癌症研究。然后，她将准备好成功竞争并获得癌症研究领域的独立终身职位。