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Human 3D Neuro-Vascular Interaction and Meningeal Lymphatic Models with Application to Alzheimer’s Disease

人体 3D 神经血管相互作用和脑膜淋巴模型在阿尔茨海默病中的应用

基本信息

批准号：
10179538
负责人：
SE HOON CHOI
金额：
$ 52.86万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
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：
2021-05-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10179538
关键词：
3-Dimensional AD transgenic mice Abeta clearance Address Affect Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Amyloid beta-Protein Astrocytes Biological Markers Biological Models Blood Blood - brain barrier anatomy Blood Cells Blood Vessels Brain Brain Chemistry Brain Pathology Cell Culture Techniques Cells Cerebral Amyloid Angiopathy Cerebrospinal Fluid Clinical Complex Deep Cervical Lymph Node Dementia Deposition Development Disease Progression Disease model Elderly Endothelial Cells Environment Event Extracellular Matrix Genetic Transcription Goals Healthcare Human Immune Impaired cognition Impairment In Vitro Intercellular Fluid Intervention Liquid substance Lymphatic Lymphatic System Lymphatic function Lymphocyte Meningeal lymphatic system Meninges Microfluidic Microchips Microfluidics Microglia Modeling Molecular Monitor Neuraxis Neurodegenerative Disorders Neurofibrillary Tangles Neurons Organoids Pathogenicity Pathologic Pathology Pathway interactions Peptides Pericytes Phagocytosis Pharmaceutical Preparations Physiological Population Process Property Role Senile Plaques Structure System Technology Testing Therapeutic Intervention United States age related aging population antibody test brain parenchyma candidate marker cell behavior cell type design disease-in-a-dish drug discovery experience human disease hyperphosphorylated tau in vitro Model in vivo induced pluripotent stem cell interest interstitial lymphatic circulation lymphatic dysfunction lymphatic vessel microfluidic technology neurovascular neurovascular unit new therapeutic target stem cells tau Proteins three-dimensional modeling tool transcriptome sequencing

项目摘要

PROJECT SUMMARY As the elderly population increases, the number of people with Alzheimer's disease (AD) is rising rapidly. There is, therefore, a growing interest in the development of in vitro human disease models to better understand and study the physiological and pathological mechanisms associated with AD. Emerging evidence has implicated an early breakdown of the BBB in AD patients, even before the cognitive decline and brain pathology. In addition, meningeal lymphatics are responsible for clearance of Aβ peptides from the brain parenchyma, and disruption of meningeal lymphatics in AD transgenic mice accelerates Aβ deposition in the meninges, aggravates parenchymal Aβ accumulation, and induces cognitive impairment. Yet, our understanding of the role of fluid transport across the BBB, through the brain parenchyma, and exiting via the lymphatic system is poorly understood. Therefore, the development of physiologically realistic human neural cell culture models of AD with a neurovascular unit and meningeal lymphatic vessels is urgently needed to dissect molecular mechanisms underlying the pathogenic cascade of AD and accelerate the discovery of new AD drugs. Building on our extensive set of preliminary and related studies, we propose to develop a three-dimensional (3D) in vitro model by integrating BBB, meningeal lymphatics, and stem-cell-derived AD cell culture to closely mimic the AD brain environment. With this model, we aim to identify AD-specific mechanisms underlying pathophysiological changes in the BBB, meningeal lymphatics, and Aβ clearance. Our 3D AD model will be useful for not only studying the mechanisms of AD progression but also for drug discovery in a human brain-like environment.

项目总结随着老年人口的增加，阿尔茨海默病(AD)患者的数量正在迅速上升。那里因此，人们对体外人类疾病模型的开发越来越感兴趣，以更好地理解和研究阿尔茨海默病的生理和病理机制。新出现的证据表明，阿尔茨海默病患者早期血脑屏障的破坏，甚至在认知功能下降和脑病理之前。此外, 脑膜淋巴管负责Aβ多肽从脑实质中的清除和破坏 AD转基因小鼠脑膜淋巴管的缺失加速Aβ在脑膜的沉积，加重实质β积聚，并导致认知障碍。然而，我们对流体作用的理解通过血脑屏障、脑实质和淋巴系统的转运很差。明白了。因此，AD生理现实的神经细胞培养模型的建立迫切需要神经血管单位和脑膜淋巴管来剖析分子机制。研究阿尔茨海默病的致病级联反应，加速AD新药的发现。建立在我们的广泛的初步研究和相关研究，我们建议建立一个三维(3D)的体外模型通过整合血脑屏障、脑膜淋巴管和干细胞来源的AD细胞培养来接近模拟AD脑环境。通过这个模型，我们的目标是确定AD的病理生理变化的特定机制血脑屏障、脑膜淋巴管和β清除。我们的3D AD模型将不仅用于研究这不仅有助于研究阿尔茨海默病的进展机制，也有助于在类人脑环境中进行药物发现。