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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：
10396570
负责人：
SE HOON CHOI
金额：
$ 51.63万
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/10396570
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 Antibodies 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 Persons Phagocytosis Pharmaceutical Preparations Physiological Population Process Property Role Senile Plaques Structure System Technology Testing Therapeutic Intervention United States age related aging population 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.

项目摘要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增加。那里因此，人们对体外人类疾病模型的发展越来越感兴趣，以更好地理解和研究AD的生理和病理机制。新出现的证据表明在AD患者中，甚至在认知能力下降和脑病理学之前，BBB的早期破坏。此外，本发明还提供了一种方法，脑膜分泌物负责从脑实质中清除Aβ肽， AD转基因小鼠中脑膜炎细胞的增加加速了Aβ在脑膜中的沉积，实质Aβ蓄积，并诱导认知障碍。然而，我们对流体作用的理解穿过BBB、穿过脑实质并经由淋巴系统离开的转运是很差的明白因此，生理上现实的AD人神经细胞培养模型的开发，迫切需要神经血管单位和脑膜淋巴管来剖析分子机制潜在的致病级联的AD和加速发现新的AD药物。充分发挥两国通过大量的初步和相关研究，我们建议开发一种三维（3D）体外模型通过整合血脑屏障、脑膜炎细胞和干细胞来源的AD细胞培养物来密切模拟AD脑环境通过这个模型，我们的目标是确定AD的具体机制的病理生理变化 BBB、脑膜炎和Aβ清除率。我们的3D AD模型不仅可用于研究 AD进展的机制，而且还用于在人脑样环境中的药物发现。