Engineering Human Brain Neurovascular Niche for Modeling Brain Diseases

工程人脑神经血管生态位以模拟脑疾病

基本信息

批准号：
10478162
负责人：
Jessica Elaine Young
金额：
$ 22.06万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10478162
关键词：
3-Dimensional Address Adherent Culture Alzheimer&apos s Disease Alzheimer&apos s disease patient Alzheimer&apos s disease related dementia Architecture Biochemical Bioinformatics Biological Biology Biophysics Blood Blood - brain barrier anatomy Blood Circulation Blood Vessels Brain Brain Diseases Cardiac Output Cell Communication Cell Survival Cells Clinical Trials Complex Coupling Cues Disease Engineering Failure Functional disorder Future Goals Health Human Human Engineering Immune Inflammation Mediators Inflammatory Lead Length Microglia Modeling Molecular Monitor Mutation Nerve Degeneration Neuraxis Neurodegenerative Disorders Neurons Organoids Outcome Pathogenesis Pathology Patients Perfusion Pericytes Phenotype Pluripotent Stem Cells Pre-Clinical Model Prevention Research Role Source Structure Swedish mutation Technology Testing Time Vascular Diseases aging brain blood-brain barrier disruption cell type cerebral microvasculature conditioning design human pluripotent stem cell improved in vivo induced pluripotent stem cell insight interstitial man nervous system disorder neural circuit neuroinflammation neuropathology neurovascular neurovascular unit process optimization relating to nervous system stem cell biology stem cell technology stem cells success symposium therapeutic development therapeutic target

项目摘要

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.

神经血管单元（NVU）调节大脑中有效的血液支持和神经元功能。它的功能障碍或细分与包括阿尔茨海默氏病（AD）和包括的多种神经系统疾病有关有助于发起和加剧神经病理学。但是，基本的生物学机制对于设计有效的预防或治疗的设计，保持不足。不足的进展由于缺乏适当且手工的前人脑的临床模型，可以概括复杂的细胞，生物物理和生化间人类NVU的行动。为了应对这些挑战，我们已经建立了一个跨学科团队在微血管工程和血管生物学以及干细胞和神经生物学方面有关重建Hu- 在正常情况和患病状况下，人脑脑神经血管生态位了解NVU功能。我们将利用我们的协同功能来通过灌注型通过脑类正弦技术生成NVU 脑微血管。我们将检验以下假设，即血管细胞和复杂的神经回路相互作用时间和空间，灌注脑微血管都为神经元提供成熟线索，而GE- 神经元的网络背景会影响NVU中血管和神经元功能的功能。我们将询问血管化脑器官中不同细胞类型的分子和细胞变化，以及如何这可能与使用AD患者衍生的IPSC相关的疾病状态。一旦成功，这个项目将脱颖而出速丝和利用新的血管工程技术，干细胞生物学和生物信息学以开发和了解用于建模神经退行性疾病的神经血管单元的结构和功能，这进一步发展了热发育。