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

这个小型企业技术转让(STTR)第一阶段项目的更广泛影响是创建一个药物发现平台，该平台将在过程的早期快速筛选可以进入中枢神经系统(CNS)的候选疗法。其目标是通过提供药物可以通过血/脑屏障(BBB)的高度保证，将因未能进入血脑屏障而最终失败的漫长而昂贵的临床试验降至最低。该项目将促进发现治疗严重脑相关疾病的下一代介入疗法，并将极大地造福于与目前难以或不可能用现有方法治疗的衰弱疾病作斗争的患者和家庭。早期筛查血脑屏障渗透的能力是必要的。据估计，2%的小分子药物和没有大分子的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代表着重大的医疗成本和照顾者负担。拟议的项目重点是模仿BBB。这项工作将利用圆柱形水凝胶为与血脑屏障相关的多种细胞的生长提供三个不同的区域，从而提供一个类似于自然系统的环境。这将提供一个高度相关的模型，以可视化生物活性分子在血脑屏障中的主动运输，从而创建用于中枢神经系统的有效的下一代疗法。其中一个目标是在为期十天的试验中显示细胞存活。此外，还将分析系统内细胞的遗传反应，以更好地了解它们的行为，并且系统的固有传导性将显示实时的细胞间通信。一旦创建了模型，将研究咖啡因通过模型屏障的传输，并将其与已知的咖啡因分子在体内如何作用的值进行比较，以开始验证系统。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.