STTR Phase I: Active Transport of Caffeine through a Blood-Brain Barrier Model

这个小企业技术转让（STTR）第一阶段项目的更广泛影响是创建一个药物发现平台，该平台将在早期快速筛选可以进入中枢神经系统（CNS）的候选治疗药物。其目标是通过提供药物可以通过血/脑屏障（BBB）的高度保证，最大限度地减少因未能进入BBB而最终失败的冗长而昂贵的临床试验。该项目将有助于发现下一代严重脑相关疾病的介入治疗方法，并将大大有利于患者和家庭对抗目前方法难以或无法治疗的衰弱性疾病。 需要早期筛查BBB渗透的能力。据估计，只有2%的小分子药物能够进入中枢神经系统治疗神经退行性疾病、多发性硬化症和中风，占全球总死亡人数的12%。这些疾病中的每一种都是主要的医疗保健费用和护理人员负担。 该项目的重点是模仿BBB。这项工作将利用圆柱形水凝胶为与BBB相关的多种类型细胞的生长提供三个不同的区域，从而提供与天然系统相似的环境。这将提供一个高度相关的模型来可视化生物活性分子穿过BBB的主动运输，以创建用于CNS的有效的下一代治疗剂。一个目标是在十天的试验中显示细胞存活。此外，将分析系统内细胞的遗传反应，以更好地了解它们的行为，系统的固有电导率将显示实时细胞间通信。一旦建立了模型，将研究咖啡因通过模型屏障的运输，并与已知的分子在体内如何作用的值进行比较，开始验证该系统。该奖项反映了NSF的法定使命，并被认为值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估来支持。

The broader impact of this Small Business Technology Transfer (STTR) Phase I project is to create a drug-discovery platform that will screen quickly and early in the process for candidate therapeutics that can enter the central nervous system (CNS). The goal is to minimize the lengthy and expensive clinical trials that ultimately fail because of their failure to enter the BBB by providing a high assurance that the drug can pass the blood/brain barrier (BBB). The project will facilitate discovering next-generation interventional treatments for serious brain-related diseases and will greatly benefit patients and families fighting debilitating diseases that are difficult or impossible to treat with current methods. The ability to screen for BBB penetration early is needed. An estimated 2% of small drug molecules and no large molecules are able to pass into CNS to treat neurodegenerative diseases, multiple sclerosis and strokes, accounting for 12% of total global deaths. Each of these diseases represents a major healthcare cost and caregiver burden. The proposed project focuses on mimicking the BBB. This work will utilize cylindrical hydrogels to provide three distinct regions for the growth of multiple types of cells related to the BBB, thereby providing an environment that is similar to the native system. This will provide a highly relevant model to visualize the active transport of bioactive molecules across the BBB to create effective, next-generation therapeutics for use in the CNS. One goal is to show cell survival throughout ten-day-long trials. Additionally, the genetic response of the cells within the system will be analyzed to better understand their behavior, and the system’s inherent conductivity will show real-time cell-to-cell communication. Once a model is created, the transport of caffeine across the model barrier will be studied and compared with known values of how the molecule acts within the body to begin validating the system.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.