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

胶质母细胞瘤血脑和血肿瘤屏障动力学的性别差异

基本信息

批准号：
10523139
负责人：
Samuel Adam Tyler Sprowls
金额：
$ 8.78万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-10 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10523139
关键词：
Animal Model Animals Astrocytes Award Blood Blood - brain barrier anatomy Blood capillaries Brain Breast Cancer Model Breast Cancer Patient Breast Cancer cell line Breast cancer metastasis Cancer Center Cancer Etiology Central Nervous System Neoplasms Cessation of life Chemotherapy and/or radiation Clinical Data Consensus Coupled Dependence Diagnosis Dose ERBB2 gene Endothelial Cells Environment Event Faculty Failure Fluorescence Focused Ultrasound Focused Ultrasound Therapy Foot Process Foundations Funding Glioblastoma Goals Imaging Techniques Institution Ionizing radiation Laboratory Research Lead Lesion Magnetic Resonance Imaging Malignant Neoplasms Malignant neoplasm of brain Mentors Mentorship Metastatic malignant neoplasm to brain Microbubbles Modeling Molecular Monitor Mus Neoplasm Metastasis Neurocognitive Deficit Neuroimmune Operative Surgical Procedures Outcome Patients Penetration Pericytes Permeability Pharmaceutical Preparations Pharmacologic Substance Pharmacology Phase Positioning Attribute Postdoctoral Fellow Pre-Clinical Model Protocols documentation Publications Radiation Radiation exposure Radiation therapy Regulation Reporting Research Research Personnel Research Project Grants Research Training Science Sex Differences Techniques Testing Therapeutic Time Tracer Training Universities West Virginia Woman Work advanced breast cancer anticancer research blood-brain tumor barrier chemotherapy clinically relevant clinically translatable cytotoxic cytotoxicity design experimental study foot human model imaging modality improved innovation malignant breast neoplasm multimodality neurovascular unit novel palliative post-doctoral training pre-clinical programs radiation effect radiation response response standard care treatment strategy tumor

项目摘要

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.

项目概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，而且通常只能提供姑息支持，但是包括手术、化疗和放射治疗。观察到电离辐射会破坏 BTB，然而，辐射暴露后分子事件的机制和时间进程仍然很差明白了。差距：目前对于放射治疗后的事件顺序尚未达成共识脑转移患者的情况，以及是否可以有效地安排化疗时间 BTB 的最大破坏。我在 F99 阶段的目标是阐明时间线，在一定范围内临床相关剂量，辐射引起的 BTB 开口，并确定是否两种批准的治疗方法，当在干扰最大的窗口给予，在适当的时机而不是在随机的。本申请中提出的培训计划采用了多种实验技术包括转移性脑癌的动物模型、多种成像方式、小规模放射治疗的使用动物、临床可转化实验的设计以及以严格和完整的方式进行科学竞争领域。该项目采用创新方法结合我们的新型脑向乳腺癌细胞行小动物放射治疗技术。在这里，我们将使用我们独特的多模态荧光和磷光成像技术可监测 BTB 渗透性的变化。我将完成这项研究在 Paul R. Lockman 博士的指导下，他的实验室拥有良好的发表记录和出色的乳腺癌脑转移领域的资金。该奖项的 F99 阶段与其余阶段一致我在 West 制药和药理学研究生项目学习了 2 年弗吉尼亚大学。我们的机构环境足以进行研究以及本提案中描述的培训，这不仅证明了该机构提供的质量和实力我们大学的教师。在这个奖项的K00阶段，我将在一个机构确定一名博士后导师拥有强大的癌症中心，使我能够进一步追求 BBB/BTB 的细胞和分子基础来自不同但互补的途径对脑转移的调节。两者结合在一起，该奖项的各个阶段将为我提供使自己成为一名成功的癌症研究员的方法并使我能够为自己的独立癌症研究实验室奠定基础研究 CNS 转移灶中 BTB 的分子相互作用和新的治疗策略。