Engineering Human Brain Neurovascular Niche for Modeling Brain Diseases

神经血管单位(NVU)调节大脑中有效的血液支持和神经元功能。它的功能障碍或 精神崩溃与多种神经疾病有关，包括阿尔茨海默病(AD)和 会引发和加剧神经病理。然而，潜在的生物学机制， 对于有效预防或治疗的设计仍缺乏足够的了解。在以下方面的进展- 在一定程度上，由于缺乏适当和可操控的预制机制，这些机制的作用有限。 可以概括复杂的细胞、生物物理和生化相互关系的人脑临床模型 在人类NVU中的行动。为了应对这些挑战，我们成立了一个跨学科的团队，由前 擅长微血管工程学和血管生物学，以及干细胞和神经生物学重建人脐静脉。 人类脑神经血管生态位，用于了解NVU在正常和疾病条件下的功能。 我们将利用我们的协同能力，通过脑器官技术产生NVU和可灌装的 脑微血管。我们将检验这样一种假设，即血管细胞和复杂的神经回路在 在时间和空间上，可灌流的脑微血管为神经元提供成熟的线索，而Ge- 神经元的磁场背景影响着NVU的血管功能和神经元功能。我们会 探讨不同细胞类型在血管化脑器质中的分子和细胞变化及其机制 这可能与使用AD患者来源的IPSCs的疾病状态有关。一旦成功，这个项目将减少- 开发和开发新的血管工程技术、干细胞生物学和生物信息学，以开发和 了解用于模拟神经退行性疾病的神经血管单位的结构和功能， 这进一步推动了治疗的发展。

Neurovascular unit (NVU) regulates efficient blood support and neuron functions in the brain. Its dysfunction or breakdown is associated with a wide variety of neurological disorders including Alzheimer’s disease (AD) and contribute to both initiating and exacerbating neuropathology. The underlying biological mechanisms, however, remain insufficiently understood for the design of effective prevention or treatment. The progress in under- standing these mechanisms has been limited, partially, due to the lack of appropriate and manipulatable pre- clinical models for human brains that can recapitulate the complex cellular, biophysical and biochemical inter- actions in human NVUs. To address these challenges, we have established an interdisciplinary team with ex- pertise in microvascular engineering and vascular biology, and stem cell and neural biology to reconstruct hu- man brain neurovascular niche for the understanding of NVU functions in both normal and diseased conditions. We will exploit our synergistic capabilities to generate NVU through brain organoids technology with perfusable brain microvessels. We will test the hypothesis that the vascular cells and complex neural circuits interact in both time and space, that perfusable brain microvessels provide maturation cues to the neurons, whereas ge- netic background of neurons influences the function of both vascular and neuron functions in the NVU. We will interrogate the molecular and cellular changes of different cell types in vascularized brain organoid and how this may be relevant to a disease state using AD patient derived iPSCs. Once successful, this project will de- velop and exploit new vascular engineering technology, stem cell biology and bioinformatics to develop and understand the structure and function of the neurovascular unit for modeling neurodegenerative diseases, which further advances therapeutic development.