Identifying targeting antibodies in an in vitro model of the human blood-brain barrier during ischemic stroke

在缺血性中风期间人血脑屏障的体外模型中识别靶向抗体

• 批准号: 10761258
• 负责人: Moriah Katt
• 金额: $ 19.7万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-27 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10761258
• 关键词: Identifying; targeting; antibodies; vitro; model

Stroke is one of the leading causes of disability and death in the US. One of the contributing factors to this is the lack of FDA approved treatments for chronic stroke. Aside from tissue plasminogen activator (tPA), there are no other approved therapeutics with disease modifying effects; current therapy is entirely focused on symptom management and rehabilitation. This is in part due to the lack of understanding of the underlying mechanisms involved, as well as the difficulty of delivering therapeutics through the blood-brain barrier (BBB) and into the brain. This project aims to address both of these difficulties through the development of a human induced pluripotent stem cell (hiPSC) derived model of the BBB incorporating hiPSC derived brain microvascular endothelial like cells (BMECs), astrocytes, and neurons. Using a 3D microvessel platform ischemia will be modeled using perturbations in shear flow, oxygen concentration, and nutrient availability. The resultant phenotype of the cells will be investigated using live cell microscopy to measure permeability of fluorescent tracer molecules, as well as morphological changes in the cells. Using this model, as well as a simplified 2D model of ischemia, a library of antibodies will be screened for improved targeting and delivery to the human ischemic brain. Finally, the antibodies identified in the screen will be tested for efficacy in delivering known non-brain penetrant neuroprotectant growth factors to the ischemic brain both in the in vitro model and in a mouse model of stroke. In summary, this project will establish a human specific model of the BBB during ischemic stroke and identify antibodies that are able to specifically target and deliver therapeutics to the ischemic region of the brain.

中风是美国致残和死亡的主要原因之一。其中一个促成因素是