DEFINING THE CELLULAR AND PHYSIOLOGICAL ROLE OF ABCA2

定义 ABCA2 的细胞和生理作用

• 批准号: 7111981
• 负责人: JODY TUCKER MACK
• 金额: $ 4.88万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7111981
• 关键词: cholesterol; genetically modified animals; human; metabolism; model; neoplasm /cancer; neoplastic cell; prostate; prostate neoplasms; role

DESCRIPTION (provided by applicant): Overexpression of the ATP binding cassette (ABC) transporter, ABCA2, has been linked to resistance to estramustine, a drug used to treat hormone-refractory prostate cancer. ABCA2 has a putative role in trafficking cholesterol, steroids and lipids into endolysosomes, suggesting a role in human disease, including cancer and atherosclerosis. To date, forced over-expression of ABCA2 in cell lines has been the only tool used to investigate its function. The studies outlined in this proposal use ABCA2-knockout and -knock-in transgenic mice to examine the role of ABCA2 in cholesterol metabolism, physiology and prostate tumor development/treatment response in mice crossed to the TRAMP mouse model of prostate carcinoma. Mouse embryonic fibroblasts (MEFs), derived from knockout and knock-in mice, and prostate cancer cells (PCS, DU145, LNCaP), stably transfected with inducible ABCA2 expression or RNA interference, will be analyzed for response to changes in ABCA2 levels. Effects of ABCA2 expression on proliferation, cholesterol trafficking and drug treatment response will be examined. The ultimate goal is to understand the cellular and physiological function of ABCA2 using transgenic animal models, MEFs and human prostate cancer cells.

描述（由申请人提供）：ATP结合盒（ABC）转运蛋白ABCA2的过表达与对治疗激素 - 难治性前列腺癌的药物的抗性有关。 ABCA2在运输胆固醇，类固醇和脂质中具有推定的作用，这表明在包括癌症和动脉粥样硬化在内的人类疾病中起作用。迄今为止，在细胞系中强迫对ABCA2的过表达是用于研究其功能的唯一工具。该提案中概述的研究使用ABCA2敲除和-KNOCK-IN转基因小鼠检查ABCA2在杂交小鼠与前列腺癌小鼠模型的小鼠中的胆固醇代谢，生理和治疗反应中的作用。将分析小鼠胚胎成纤维细胞（MEF），源自敲除和敲除小鼠，前列腺癌细胞（PCS，DU145，LNCAP），稳定地转染了诱导型ABCA2表达或RNA干扰，以分析对ABCA2水平变化的响应。将检查ABCA2表达对增生，胆固醇运输和药物治疗反应的影响。最终目标是使用转基因动物模型，MEF和人前列腺癌细胞了解ABCA2的细胞和生理功能。