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

30行摘要： 这项建议的目标是为科学界开发基于 在芯片上的器官系统上，它将能够询问乳房的神经元依赖调节器- 脑转移和相关并发症，如与血液相关的血管源性水肿 脑部屏障被破坏。脑转移(乳腺癌是第二大原因)和 他们相关的神经功能障碍尤其严重，因为他们的寿命很短。 期望值和生活质量下降。严重缺乏有效的治疗方法。 各团因血脑屏障的存在而无法运送多发性 化疗药物进入中枢神经系统(CNS)。我们将使用神经血管 单位(NVU)组织芯片，一种相当于血脑屏障的芯片上器官，包括 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 它特别适合于研究乳腺转移性脑转移的神经元调节 强调测量神经元在转移性疾病扩展中的特定作用， 移居和与之相关的转移微环境的变化。此外，我们 将NVU与乳腺厚组织生物反应器(MG-TTB)耦合作为一种 完整的主辅点肿瘤学芯片系统，用于乳房到乳房的高级研究 脑部转移。MG-TTB是本课题组研制的用于药物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、监测毒物依赖对细胞功能的改变以及药物评估 在明确的物理和化学肿瘤条件下培养的致瘤乳腺上皮细胞 微环境。MG-TTB具有相同的物理规模，并共享类似的材料和 带有NVU的硬件，将允许这些单元无缝集成，以探测主到主设备 继发性肿瘤扩散。我们的目的是验证NVU在乳房到乳房研究中的适用性。 脑转移的过程如下：1)确定神经元依赖的动态变化 乳腺癌脑转移瘤内种植对转移瘤微环境的驱动 北威州大学。2)通过评估确定神经元依赖在乳房到脑转移中的作用 它们在NVU血脑屏障肿瘤渗出中的作用。

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.