Organ-on-chip bioreactors for recreating breast to brain metastases

用于重建乳腺至脑转移瘤的器官芯片生物反应器

• 批准号: 10416014
• 负责人: LISA Joy MCCAWLEY
• 金额: $ 18.15万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-02 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10416014
• 关键词: Astrocytes; Automobile Driving; Biological Assay; Biology; Bioreactors; Blood - brain barrier anatomy; Blood Vessels; Brain; Breast; Breast Cancer Cell; Breast Epithelial Cells; Cell physiology; Chemicals; Communities; Coupled; Development; Devices; Disease; Event; Extravasation; Life Expectancy; Link; Mammary gland; Mass Spectrum Analysis; Measures; Metastatic breast cancer; Metastatic malignant neoplasm to brain; Metastatic to; Microfluidics; Modeling; Molecular; Monitor; Neoplasm Metastasis; Neuraxis; Neurologic; Neurons; Oncology; Organ; Outcome Study; Penetrance; Performance; Pericytes; Pharmaceutical Preparations; Phenotype; Process; Quality of life; Regulation; Role; Secondary to; Site; System; Technology; Therapeutic Effect; Thick; Tissue Microarray; Tissues; advanced system; base; blood-brain barrier disruption; blood-brain barrier function; brain endothelial cell; cell type; disability; ion mobility; malignant breast neoplasm; neurovascular; neurovascular unit; novel therapeutics; organ on a chip; therapeutically effective; toxicant; treatment effect; tumor; tumor microenvironment; tumorigenic; vasogenic edema

30 line summary: The objective of this proposal is to develop for the scientific community validated assays based on organ on chip systems that will enable interrogating the neuron dependent regulators of breast- to-brain metastasis and related complications such as vasogenic edema associated with blood brain barrier disruption. Brain metastases (with breast cancer being second largest cause) and their associated neurologic disabilities are particularly serious as they result in very short life expectancies and reduced quality of life. There is a significant lack of effective therapeutic regiments due to presence of blood brain barrier which precludes the delivery of multiple chemotherapeutic drugs into the central nervous system (CNS). We will use the NeuroVascular Unit (NVU) tissue chip, an organ-on-chip equivalent of the blood-brain-barrier comprised of neurons, astrocytes, brain pericytes and brain microvascular endothelial cells. We will evaluate its suitability to study the neuronal regulation of breast-to-brain metastasis with particular emphasis on measuring the specific role of neurons on metastatic disease expansion, colonization and the associated changes to the metastatic microenvironment. Furthermore, we will evaluate the NVU coupled to a Mammary Gland Thick Tissue bioreactor (MG-TTB) as a complete primary-to-secondary site oncology-on-chip system for advanced study of breast-to- brain metastasis. MG-TTB is a microfluidic bioreactor developed by our group for drug assessment of tumorigenic mammary epithelial cells that is currently in use for toxicant assessment, monitoring toxicant-dependent changes to cellular functions, and drug assessment of tumorigenic mammary epithelial cells cultured under defined physical and chemical tumor microenvironments. The MG-TTB is on the same physical scale and shares similar materials and hardware with NVU that will allow seamless integration of these units to probe primary-to- secondary tumor dissemination. Our aims to validate the suitability of NVU for study of breast-to- brain metastasis processes are as follows: 1) Determine the neuron dependent dynamic changes to metastatic tumor microenvironment driven by breast cancer brain metastases seeded within the NVU. 2) Determine the neuron dependent role into breast-to-brain metastasis by evaluating their contribution in tumor extravasation of the NVU blood brain barrier.

30行总结： 该提案的目的是为科学界开发基于验证的检测方法 在器官芯片系统上，该系统将能够询问乳腺的神经元依赖性调节器 脑转移和相关并发症，例如与血液相关的血管源性水肿 脑屏障破坏。脑转移（乳腺癌是第二大原因）和 他们相关的神经功能障碍特别严重，因为它们会导致寿命非常短 预期和生活质量下降。严重缺乏有效的治疗方法 由于血脑屏障的存在，阻碍了多种药物的输送 化疗药物进入中枢神经系统（CNS）。我们将使用神经血管 Unit (NVU) 组织芯片，​​相当于血脑屏障的器官芯片，由以下部分组成 神经元、星形胶质细胞、脑周细胞和脑微血管内皮细胞。我们将评估 它适合研究乳腺脑转移的神经元调节，特别是 强调测量神经元对转移性疾病扩展的具体作用， 定植和转移微环境的相关变化。此外，我们 将评估与乳腺厚组织生物反应器 (MG-TTB) 耦合的 NVU 作为 完整的初级到次级站点肿瘤芯片系统，用于乳腺到次级肿瘤的高级研究 脑转移。 MG-TTB是我课题组针对药物研发的微流控生物反应器 目前用于毒物的致瘤性乳腺上皮细胞的评估 评估、监测细胞功能的毒物依赖性变化以及药物评估 在特定的物理和化学肿瘤下培养的致瘤性乳腺上皮细胞 微环境。 MG-TTB 具有相同的物理尺寸并共享相似的材料和 具有 NVU 的硬件将允许这些单元无缝集成以探测初级到 继发性肿瘤播散。我们的目标是验证 NVU 对于乳腺研究的适用性 脑转移过程如下： 1）确定神经元依赖性动态变化 由乳腺癌脑转移驱动的转移性肿瘤微环境 内华达大学。 2) 通过评估确定神经元依赖性在乳腺转移中的作用 它们在 NVU 血脑屏障肿瘤外渗中的作用。