Sex Differences in Blood-Brain and Blood-Tumor Barrier Dynamics in Glioblastoma

项目摘要 转移性病变约占所有中枢神经系统肿瘤的80%。其中，乳腺癌脑转移 占所有脑转移瘤的三分之一。治疗选择很少，而且往往只提供姑息支持，但 包括手术、化疗和放射治疗。观察到电离辐射会扰乱BTB， 然而，辐射后分子事件的机制和时间进程仍然很差。 明白了。GAP：目前还没有关于放射治疗后的事件顺序的共识 脑转移瘤的患者，以及化疗是否能有效地选择时间窗 对BTB的最大破坏。我在F99阶段的目标是阐明时间线，在一系列 临床相关剂量，辐射诱导的BTB开口，并确定两种批准的治疗方法，何时 在干扰最大的时间段给药，在适当的时机给药会导致细胞毒性增加 随机的。本申请中提出的培训计划采用了各种各样的实验技术 包括脑转移癌的动物模型，多种成像方式，小剂量放射治疗的应用 动物，临床可翻译实验的设计，以及在严格和 竞争激烈的领域。这个项目使用了一种创新的方法，结合了我们新的嗜脑乳腺癌细胞 具有小动物辐射技术的线路。在这里，我们将使用我们独特的多峰荧光和 用于监测BTB通透性变化的磷光成像技术。我会完成这项研究的 在保罗·R·洛克曼博士的指导下，他的实验室拥有出色的出版记录 在乳腺癌脑转移领域的资金。该奖项的F99阶段与其余 我有两年的时间在West攻读药学和药理学研究生课程 弗吉尼亚大学。我们的制度环境非常适合进行这项研究。 和本提案中描述的培训，这不仅表明了 我们大学的教职员工。在这个奖项的K00阶段，我将确定一个机构的博士后导师 强大的癌症中心使我能够进一步研究BBB/BTB的细胞和分子基础 从一个不同但互补的途径对脑转移进行监管。两者结合在一起， 这个奖项的各个阶段将为我提供将自己确立为一名成功的癌症研究人员的手段 并使我能够为我自己的独立癌症研究实验室奠定基础 BTB在中枢神经系统转移灶中的分子相互作用及新的治疗策略的研究。

Project Summary Metastatic lesions encompass approximately 80% of all CNS tumors. Of that, breast cancer brain metastasis comprises a third of all brain metastases. Treatment options are few and often only offer palliative support, but include surgery, chemotherapy, and radiation therapy. Ionizing radiation is observed to disrupt the BTB, however the mechanism and time course of molecular events following radiation exposure remains poorly understood. Gap: There is currently no consensus on the sequence of events following radiation therapy for patients with brain metastases, and whether or not chemotherapy can be effectively timed with windows of greatest disruption of the BTB. My goal during the F99 phase is to elucidate the time line, at a range of clinically relevant doses, of radiation-induced BTB openings and determine if two approved therapeutics, when given at windows of greatest disruption, lead to increased cytotoxicity when timed competently rather than at random. The training plan set forth in this application employs a wide variety of experimental techniques including animal modeling of metastatic brain cancer, multiple imaging modalities, use of radiation in small animals, design of clinically translatable experiments, and conducting science with integrity in a rigorous and competitive field. This project uses an innovative approach combining our novel brain tropic breast cancer cell lines with small animal radiation techniques. Herein, we will use our unique multimodal fluorescence and phosphorescent imaging techniques to monitor changes in BTB permeability. I will complete this research under the mentorship of Dr. Paul R. Lockman, whose lab boasts a strong publication record with excellent funding in the field of brain metastases of breast cancer. The F99 phase of this award aligns with the remaining 2 years I have of my time in the Pharmaceutical and Pharmacological Sciences graduate program at West Virginia University. Our institutional environment is more than adequately positioned to conduct the research and training described in this proposal, which more than demonstrates the quality and strength offered by the faculty at our university. In the K00 phase of this award, I will identify a postdoctoral mentor at an institution with a strong cancer center allowing me to pursue further the cellular and molecular foundation of BBB/BTB regulation in brain metastases from a different, but complementary avenue. Combined together, the two phases of this award will provide me with the means to establish myself as a successful cancer researcher and enable me to lay the foundation for my own independent cancer research laboratory predicated on the study of the molecular interworking of the BTB in CNS metastatic lesions and novel treatment strategies.