Modulation of BBB to Enhance CNS Chemotherapy

描述：（由申请人提供）本申请是一个请求， 指导研究科学家发展奖（KO 1）进一步博士.娜塔莉 爱丁顿在抗癌药物输送领域的研究， 药代动力学爱丁顿博士的长期目标是提高药物输送 通过调节血液中固有的因素， 脑屏障生理学，用于阻碍药物运输。主要的重点 她的研究主要是阐明潜在的药代动力学相关 在药物递送中重要的药物分布因素， 处分为此，她的研究计划的目标是更好地 了解血脑屏障（BBB）的机械活动， 药物转运和调节这些因子以增强药物递送。两 最小化药物穿过BBB的转运的因素是：（1）多药转运， 耐药蛋白，P-糖蛋白，有效地将药物从细胞中排出。 在BBB的脑，和（2）在BBB中的紧密连接的存在， 最小化药物通过BBB进入脑的细胞旁转运。 通过减少P-糖蛋白介导的药物调节血脑屏障 流出或可逆性开放紧密连接，理论上应增强 药物输送到大脑。这项建议寻求培训，以追求两个 研究项目：一个项目旨在检查一系列的能力， 化合物，烯胺酮，在逆转P-gp介导的 阿霉素第二个项目考察了闭锁小带的能力， 毒素是一种可逆性开放紧密连接的蛋白质， 将一系列抗癌药物输送到大脑。 一个指导研究科学家奖将允许博士爱丁顿扩大她的 在抗癌药物输送和药代动力学领域的专业知识， 专注于药物输送到大脑的潜在机制。 为了获得上述领域的专业知识，她将接受以下人员的指导： Drs. Peter Melera和Yanto Lunardi-Iskandar。培训经验将 包括获得优化细胞培养技术的经验，蛋白质印迹 P-gp在不同细胞中的定量分析、转染技术 线，共聚焦显微镜检查运输在细胞水平上， 啮齿动物神经胶质瘤模型的开发。这些领域的经验将 提高她的研究技能和能力，使她能够作出贡献， 在抗癌药物输送和药代动力学领域进行研究。

DESCRIPTION: (provided by Applicant) This application is a request for a Mentored Research Scientist Development Award (KO1) to further Dr. Natalie Eddington's research in the area of anticancer drug delivery and pharmacokinetics. Dr. Eddington's long term goal is to enhance drug delivery of anticancer agents to the brain by modulating factors inherent in blood brain barrier physiology that serve to hinder drug transport. The main focus of her research has been to elucidate underlying pharmacokinetic related factors of drug distribution that are important in drug delivery and disposition. To that end, the goals of her research program are to better understand mechanistic activity at the blood brain barrier (BBB) that limit drug transport and modulate these factors to enhance drug delivery. Two factors that minimize drug transport across the BBB are: (1) the multidrug resistant protein, P-glycoprotein, which effectively ejects drugs out of the brain at the BBB, and (2) the presence of tight junctions in the BBB, which minimizes paracellular transport of drugs into the brain via the BBB. Modulation of the blood brain barrier by reducing P-glycoprotein mediated drug efflux or by reversibly opening tight junctions should theoretically enhance drug delivery to the brain. This proposal seeks training to pursue two research projects: One project seeks to examine the ability of a series of compounds, the enaminones, in reversing the P-gp mediated efflux of doxorubicin. The second project examines the ability of Zonula Occludens Toxin, a protein which can reversibly open the tight junctions, in enhancing drug delivery of a series of anticancer agents to the brain. A Mentored Research Scientist Award will allow Dr. Eddington to expand her expertise in the area of anticancer drug delivery and pharmacokinetics by focusing on the underlying mechanisms involved in drug delivery to the brain. In order to gain expertise in the areas mentioned, she will be mentored by Drs. Peter Melera and Yanto Lunardi-Iskandar. The training experience will involve gaining experience in optimizing cell culture techniques, Western Blot Analysis with quantitation, transfection techniques of P-gp into various cell lines, confocal microscopy to examine transport at the cellular level, and the development of a rodent glial tumor model. Experience in these areas will enhance her research skills and capabilities and will allow her to contribute to research in the area of anticancer drug delivery and pharmacokinetics.