癌症多药耐药性的结构基础-猫眼课题宝

癌症多药耐药性的结构基础

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

项目状态：

已结题

起止时间：

2005-06-03 至 2011-05-31

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

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英文摘要

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.

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