Modulation of BBB to Enhance CNS Chemotherapy

描述：(由申请人提供)本申请是一份申请 指导研究科学家发展奖(KO1)以进一步提升Natalie博士 爱丁顿在抗癌药物输送领域的研究和 药物动力学。艾丁顿博士的长期目标是加强药物输送 通过调节血液中固有的因子将抗癌药物输送到大脑 阻碍药物运输的脑屏障生理学。主要关注点 她的研究一直是为了阐明潜在的药代动力学 药物分布的因素，这些因素对药物输送和 性情。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素，以加强药物输送。二 将药物跨血脑屏障转运降至最低的因素有：(1)多种药物 耐药蛋白，P-糖蛋白，它有效地将药物排出体外 血脑屏障处的大脑，以及(2)血脑屏障内存在紧密连接，这 最大限度地减少药物通过血脑屏障进入大脑的细胞旁运输。 降低P-糖蛋白介导的药物对血脑屏障的调节 理论上，外流或通过可逆地打开紧密连接应该会增强 将药物输送到大脑。这项提案寻求培训，以追求两个 研究项目：其中一个项目试图检验一系列 氨基酮类化合物逆转P-gp介导的血管外流 阿霉素。第二个项目是检查闭锁小带的能力 毒素，一种可以可逆地打开紧密连接的蛋白质，在增强 将一系列抗癌药物输送到大脑。 导师研究科学家奖将允许爱丁顿博士扩大她的 在抗癌药物输送和药代动力学领域的专业知识 重点研究药物向大脑输送的潜在机制。 为了获得上述领域的专业知识，她将接受以下方面的指导 彼得·梅雷拉博士和扬托·卢纳尔迪-伊斯坎达博士。培训经验将会 在优化细胞培养技术方面获得经验，Western Blot P-gp在不同细胞中的定量分析和转染技术 线，共聚焦显微镜，以检查细胞水平的运输，以及 鼠脑胶质瘤模型的建立。在这些领域的经验将 增强她的研究技能和能力，并将使她做出贡献 在抗癌药物传递和药代动力学方面进行研究。

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.