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：
10615081
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/10615081
关键词：
3-Dimensional AD transgenic mice Abeta clearance Acceleration 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 Central Nervous System 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 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.

项目概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。因此，人们对开发体外人类疾病模型越来越感兴趣，以更好地理解和研究与 AD 相关的生理和病理机制。 AD 患者的 BBB 早期崩溃，甚至发生在认知能力下降和大脑病变之前。脑膜淋巴管负责从脑实质中清除 Aβ 肽，并破坏 AD转基因小鼠脑膜淋巴管的减少会加速Aβ在脑膜中的沉积，加重然而，我们对液体作用的理解还不够。穿过血脑屏障、脑实质并通过淋巴系统排出的运输很差因此，开发符合生理学的 AD 人类神经细胞培养模型。迫切需要神经血管单元和脑膜淋巴管来剖析分子机制 AD 致病级联的基础并加速新 AD 药物的发现。通过一系列广泛的初步和相关研究，我们建议开发三维 (3D) 体外模型通过整合 BBB、脑膜淋巴管和干细胞衍生的 AD 细胞培养物来密切模仿 AD 大脑通过这个模型，我们的目标是确定 AD 病理生理变化的特异性机制。我们的 3D AD 模型不仅可用于研究 BBB、脑膜淋巴管和 Aβ 清除。 AD 进展的机制，也可用于类人脑环境中的药物发现。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Interstitial flow promotes the formation of functional microvascular networks in vitro through upregulation of matrix metalloproteinase-2.

间质流动通过基质金属蛋白酶-2 的上调促进体外功能性微血管网络的形成。

DOI：
发表时间：
2022-10-21
期刊：
影响因子：
19
作者：
Zhang, Shun;Wan, Zhengpeng;Pavlou, Georgios;Zhong, Amy X;Xu, Liling;Kamm, Roger D
通讯作者：
Kamm, Roger D

Microphysiological Neurovascular Barriers to Model the Inner Retinal Microvasculature.

用于模拟视网膜内微脉管系统的微生理神经血管屏障。

DOI：
发表时间：
2022-01-24
期刊：
影响因子：
0
作者：
Maurissen, Thomas L;Pavlou, Georgios;Bichsel, Colette;Villaseñor, Roberto;Kamm, Roger D;Ragelle, Héloïse
通讯作者：
Ragelle, Héloïse

与年龄相关的脑膜免疫改变导致中枢神经系统淋巴引流受损。

DOI：
发表时间：
2023-07-03
期刊：
影响因子：
0
作者：
Rustenhoven, Justin;Pavlou, Georgios;Storck, Steffen E;Dykstra, Taitea;Du, Siling;Wan, Zhengpeng;Quintero, Daniel;Scallan, Joshua P;Smirnov, Igor;Kamm, Roger D;Kipnis, Jonathan
通讯作者：
Kipnis, Jonathan

Microfluidic-Based Reconstitution of Functional Lymphatic Microvasculature: Elucidating the Role of Lymphatics in Health and Disease.

基于微流控的功能性淋巴微脉管系统重建：阐明淋巴管在健康和疾病中的作用。

DOI：
发表时间：
2024-02
期刊：
影响因子：
0
作者：
Serrano, Jean C;Gillrie, Mark R;Li, Ran;Ishamuddin, Sarah H;Moeendarbary, Emad;Kamm, Roger D
通讯作者：
Kamm, Roger D

Accelerating the in vitro emulation of Alzheimer's disease-associated phenotypes using a novel 3D blood-brain barrier neurosphere co-culture model.

使用新型 3D 血脑屏障神经球共培养模型加速阿尔茨海默病相关表型的体外模拟。

DOI：
发表时间：
2023
期刊：
影响因子：
0
作者：
Ko, Eunkyung Clare;Spitz, Sarah;Pramotton, Francesca Michela;Barr, Olivia M;Xu, Ciana;Pavlou, Georgios;Zhang, Shun;Tsai, Alice;Maaser;Jorfi, Mehdi;Choi, Se Hoon;Tanzi, Rudolph E;Kamm, Roger D
通讯作者：
Kamm, Roger D