In Vitro Culture Model of the Human Blood-Brain Barrier

描述(由申请人提供)： 血和脑之间的溶质分配受到脑毛细血管内皮细胞的血脑屏障(BBB)的严格调控。虽然血脑屏障在阻止大脑中不必要或有害的分子方面发挥了重要作用，但它在向大脑输送包括抗癌、抗生素或抗精神病药物在内的治疗药物方面构成了一个具有挑战性的问题。相反，防止潜在的破坏性分子克服血脑屏障也是一个日益严重的问题，特别是当遇到外源化合物的组合时。因此，医学和制药科学家越来越需要快速、可靠的人血脑屏障体外模型，用于临床前安全性和有效性筛选。为了满足这一尚未满足的需求，将开发一种基于人内皮细胞的体外血脑屏障模型。将人内皮细胞与人星形胶质细胞在特定的无血清介质中共培养在涂有细胞外基质材料的微孔膜上，以产生具有血脑屏障特性的紧密单层内皮细胞。该模型将在第一阶段描述血脑屏障功能的重要属性，包括功能紧密连接的形成和功能外排转运蛋白的表达。进一步的表征和验证将在Il阶段进行，该模型将用于研究BBB功能的调制策略。

DESCRIPTION (provided by applicant): Solute distribution between blood and brain is strictly regulated by the blood-brain barrier (BBB) at brain capillary endothelial cells. While the BBB performs an important function in keeping unnecessary or harmful molecules from the brain, it poses a challenging problem in delivering therapeutics, including anticancer, antibiotic or antipsychotic drugs into the brain. Conversely, preventing potentially damaging molecules from overcoming the BBB is also an increasing problem, especially when combinations of xenobiotics are encountered. Medical and pharmaceutical scientists therefore have a growing need for rapid, reliable in vitro models of the human BBB for preclinical safety and efficacy screening. To fulfill this unmet need, an in vitro BBB model based on human endothelial cells will be developed. Human endothelial cells will be co-cultured with human astrocytes on a microporous membrane coated with extracellular matrix material in defined serum-free medium to produce a tight monolayer of endothelial cells possessing BBB properties. The model will be characterized in Phase I with respect to important attributes of the BBB function including formation of functional tight junctions and expression of functional efflux transporters. Further characterization and validation will proceed during Phase Il, and the model will be used to study strategies for modulation of BBB function.