In Vitro Culture Model of the Human Blood-Brain Barrier

描述（由申请人提供）： 溶质在血液和脑之间的分布受到脑毛细血管内皮细胞处的血脑屏障（BBB）的严格调节。虽然BBB在将不必要或有害的分子从大脑中清除方面发挥着重要作用，但它在将包括抗癌、抗生素或抗精神病药物在内的治疗药物递送到大脑中方面提出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，特别是当遇到外源性物质的组合时。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。为了满足这一未满足的需求，将开发基于人内皮细胞的体外BBB模型。将人内皮细胞与人星形胶质细胞在包被有细胞外基质材料的微孔膜上在限定的无血清培养基中共培养，以产生具有BBB特性的紧密单层内皮细胞。该模型将在I期中表征BBB功能的重要属性，包括功能性紧密连接的形成和功能性外排转运蛋白的表达。进一步的表征和验证将在II期进行，并且该模型将用于研究调节BBB功能的策略。

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.