Modeling Anthracycline-Induced Cognitive Impairment Using iPSC-Derived Brain-On-Chips

项目摘要 阿霉素（DOX）是蒽环类的一种成熟且高效的化疗药物， 通常用于治疗多种恶性肿瘤。越来越多的证据表明， 接受蒽环类药物化疗的患者表现出更严重的认知障碍， 接受非蒽环类药物治疗。然而，由于功能性人脑的相对不可及性 尽管研究的组织中，DOX诱导的认知障碍的潜在机制仍然很差 明白为此，在这个以阿尔茨海默氏症为重点的行政补充中，我们的目标是使用患者特异性 在2D和3D培养物中诱导多能干细胞（iPSC）衍生的神经血管细胞以模拟这种疾病 培养皿中的表型。在目标1中，我们将产生iPSC-脑周细胞和iPSC-脑微血管内皮细胞。 细胞（BMEC），并测试细胞活力，氧化应激， 生理性DOX前后两种血管细胞类型的线粒体功能和细胞因子分泌 治疗在目标2中，我们将使用脑芯片来生成体外3D血脑屏障样结构（ 神经血管单位），其包含同基因iPSC-周细胞、iPSC-BMEC、iPSC-星形胶质细胞和iPSC-神经元 作为研究细胞-细胞相互作用对DOX诱导的BBB的影响的更生理相关的平台 完整性破坏。总的来说，我们将建立的平台可以作为一个原则证明，以测试药物 可以改善认知缺陷或由癌症引起的各种类型的神经退行性疾病的靶点- 相关治疗。

PROJECT SUMMARY Doxorubicin (DOX), a well-established and highly effective chemotherapy drug of the anthracycline class, is commonly used to treat multiple malignancies. Accumulating evidence shows that cancer patients who underwent anthracycline-based chemotherapy showed more severe cognitive impairment than those who received non-anthracycline regimens. However, due to the relative inaccessibility of functional human brain tissues for research, the underlying mechanisms of DOX-induced cognitive impairment remain poorly understood. To that end, in this Alzheimer’s-focused administrative supplement, we aim to use patient-specific induced pluripotent stem cell (iPSC)-derived neurovascular cells in 2D and 3D cultures to model this diseased phenotype in a dish. In Aim 1, we will generate iPSC-brain pericytes and iPSC-brain microvascular endothelial cells (BMECs) from 10 DOX-insensitive and 10 DOX-sensitive patients, and test cell viability, oxidative stress, mitochondrial function, and cytokine secretion in both vascular cell types before and after physiological DOX treatment. In Aim 2, we will use brain-on-chips to generate an in vitro 3D blood-brain barrier-like structure (the neurovascular unit) comprising of isogenic iPSC-pericytes, iPSC-BMECs, iPSC-astrocytes, and iPSC-neurons as a more physiological relevant platform to investigate the effects of cell-cell interaction on DOX-induced BBB integrity disruption. Overall, the platform we will be establishing can serve as a proof-of-principle to test druggable targets that can ameliorate cognitive deficits or various types of neurodegenerative diseases caused by cancer- related treatments.