3D Models of the Blood-Brain Barrier for Studying Trauma-Induced Cerebral and Systemic Injuries

用于研究创伤引起的脑损伤和全身损伤的血脑屏障 3D 模型

• 批准号: 10711489
• 负责人: Ying Zheng
• 金额: $ 46.25万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-03 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10711489
• 关键词: 3-Dimensional; Abeta clearance; Abeta synthesis; Acceleration; Acute; Affect; Alzheimer' s Disease; Amyloid beta-Protein; Astrocytes; Autopsy; Biochemical; Bioinformatics; Biological Assay; Blood; Blood - brain barrier anatomy; Blood Vessels; Brain; Cell physiology; Cells; Central Nervous System; Cerebral hemisphere hemorrhage; Cerebrovascular Disorders; Cerebrovascular system; Cerebrum; Coculture Techniques; Complex; Craniocerebral Trauma; Data; Deposition; Development; Diffuse; Disease; Endothelial Cells; Endothelium; Engineering; Exposure to; Extracellular Fluid; Extravasation; Funding; Future; Human; Immunofluorescence Immunologic; In Vitro; Inflammation; Inflammatory; Injury; Intracranial Hemorrhages; Ischemia; Lead; Link; Machine Learning; Microglia; Modeling; Mutation; Neurons; Organoids; Parents; Pathway interactions; Patients; Perfusion; Pericytes; Permeability; Pharmaceutical Preparations; Phosphotransferases; Plasma; Production; Recording of previous events; Risk; Role; Sampling; Senile Plaques; Site; Stimulus; Structure; TBI Patients; Technology; Thrombin; Tissues; Trauma; Traumatic Brain Injury; Vascular Dementia; Vascular Diseases; Vascularization; Work; abeta accumulation; abeta deposition; blood-brain barrier disruption; brain cell; cell injury; cell type; chronic traumatic encephalopathy; experimental study; extracellular vesicles; hyperphosphorylated tau; in vivo; kinase inhibitor; nervous system disorder; neurovascular; neurovascular injury; neurovascular unit; parent project; prevent; protein TDP-43; single-cell RNA sequencing; stem cell biology; success; therapeutic development; three-dimensional modeling; transcriptomics

Abstract Traumatic brain injury (TBI) and Alzheimer's disease (AD) are two devastating neurological disorders with a complex relationship. Studies have shown that patients with a history of moderate or severe TBI have a two to four-fold increased risk of developing AD compared to those with no history of head injury. The mechanistic link between two disorders is not well understood. Both diseases show cerebrovascular dysfunction, which would be a causal link between TBI and the subsequent development of vascular dementia and AD. Patients with TBI suffer initial acute injuries, which disrupts the structural integrity of the brain and brain vasculature. Such disruption leads to further breakdown of the blood brain barrier (BBB). Studies of postmortem brains of TBI showed diffuse amyloid beta (Aβ) plaques in autopsies after acute injuries. It appears that TBI-induced neurovascular injuries could accelerate production and perivascular accumulation of amyloid-beta (Aβ), leading to blood brain barrier damage and inducing a deleterious feed- forward loop. However, it is still unclear which mechanisms lead to Aβ accumulation in TBI. We hypothesize that vascular leakage and exposure to plasma factors induce the increased production of Aβ in neurons and decreased clearance of Aβ from neurovascular niche. In this supplement, we propose a complementary project to study the consequent effect of vascular disruption on neuronal cell function and identify the role of plasma factors on Aβ production from neuronal cells in brain organoids we differentiation from hiPSCs. We will perform these experiments in isolated organoids and in organoids co-cultured at the vascular interface. We will identify how plasma factors of TBI patients affect Aβ production hiPSC-derived neurons. We will also establish a BBB model comprised of vascularized brain organoids and evaluate the role of vascular dysfunction on Aβ deposition and accumulation around the BBB. The success of the project will provide important information in mechanistic link between the TBI and initiation of AD, and will have numerous implications in future neurovascular engineering approaches and therapeutic development to prevent TBI induced AD.

抽象的 创伤性脑损伤（TBI）和阿尔茨海默氏病（AD）是两种毁灭性神经系统疾病 复杂的关系。研究表明，具有现代或重度TBI病史的患者有两个 与没有头部受伤史的人相比，发展广告的风险增加了四倍。这 两种疾病之间的机械联系尚不清楚。两种疾病均显示脑血管 功能障碍，这将是TBI与随后的血管发展之间的因果关系 痴呆和广告。 TBI患者最初急性损伤，这破坏了 大脑和大脑脉管系统。这种破坏导致血脑屏障（BBB）进一步崩溃。 急性后尸检的TBI后大脑的研究显示了弥漫性淀粉样β（Aβ）斑块 受伤。 TBI诱导的神经血管损伤似乎可以加速产生和血管周围 淀粉样蛋白β（Aβ）的积累，导致血脑屏障损伤，并引起有害的进给 向前循环。但是，尚不清楚哪种机制导致Aβ在TBI中的积累。我们假设 血管泄漏和暴露于血浆因子会导致神经元中Aβ产生的增加， 从神经血管生态位的Aβ清除率降低。在此补充中，我们提出了一个完整的 研究血管破坏对神经元细胞功能的影响的项目，并确定 来自脑器官中神经元细胞Aβ产生的血浆因子我们与HIPSC分化。我们 将在分离的类器官和在血管界面共培养的类器官中执行这些实验。 我们将确定TBI患者的血浆因子如何影响Aβ产生HIPSC衍生的神经元。我们将 还建立了完成血管化脑器官的BBB模型，并评估血管的作用 BBB周围的Aβ沉积和积累的功能障碍。该项目的成功将提供 TBI与AD计划之间的机械链接中的重要信息，并将拥有许多 未来神经血​​管工程方法和治疗性开发的影响，以防止TBI 诱导的AD。