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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：
10303483
负责人：
Jessica Elaine Young
金额：
$ 26.48万
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 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10303483
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.

神经血管单位（NVU）调节大脑中有效的血液支持和神经元功能。其功能障碍或神经衰弱与多种神经系统疾病有关，包括阿尔茨海默病（AD）和导致神经病理学的开始和恶化。然而，潜在的生物学机制，对于设计有效的预防或治疗仍然没有充分的了解。在以下方面取得的进展- 长期以来，这些机制一直受到限制，部分原因是缺乏适当的和可操作的预- 人类大脑的临床模型，可以概括复杂的细胞，生物物理和生物化学间，在人类NVU中的行为。为了应对这些挑战，我们建立了一个跨学科的团队，擅长微血管工程和血管生物学，以及干细胞和神经生物学，以重建人类人脑神经血管生态位，以了解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，通过脑类器官技术产生NVU，脑微血管我们将检验血管细胞和复杂的神经回路相互作用的假设，无论是时间还是空间，灌注脑微血管为神经元提供成熟线索，而ge- 神经元的遗传背景影响NVU中血管和神经元的功能。我们将询问血管化脑类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患者来源的iPSC的疾病状态有关。一旦成功，该项目将... 发展和利用新的血管工程技术、干细胞生物学和生物信息学，了解神经血管单位的结构和功能，用于模拟神经退行性疾病，这进一步推进了治疗发展。