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

30行摘要： 本提案的目的是为科学界开发基于以下方面的经验证的测定方法： 在芯片系统上的器官，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，如血管源性水肿与血液 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，因为他们导致非常短的寿命 预期寿命和生活质量下降。严重缺乏有效的治疗方法 由于血脑屏障的存在， 化疗药物进入中枢神经系统（CNS）。我们将使用神经血管 NVU组织芯片，一种相当于血脑屏障的器官芯片， 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 其适用于研究乳腺至脑转移的神经调节， 强调测量神经元对转移性疾病扩展的特定作用， 定植和转移微环境的相关变化。而且我们 将评价与乳腺厚组织生物反应器（MG-TTB）耦合的NVU， 完整的原发至继发部位肿瘤芯片系统，用于乳腺癌的高级研究， 脑转移MG-TTB是本课题组研制的一种微流控生物反应器， 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和药物评估 致瘤性乳腺上皮细胞在确定的物理和化学肿瘤下培养 微环境MG-TTB具有相同的物理规模，使用类似的材料， 硬件与NVU，将允许这些单位的无缝集成，以探测主要到 继发性肿瘤扩散。我们的目的是验证NVU对乳腺癌研究的适用性， 脑转移过程如下：1）确定神经元依赖性的动态变化 转移性肿瘤微环境由乳腺癌脑转移驱动， NVU。2)通过评估确定神经元依赖性在乳腺-脑转移中的作用 它们在NVU血脑屏障的肿瘤外渗中的作用。

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.