I-Corps: An in vivo central nervous system drug screening platform with noninvasive imaging

这个I-Corps计划的更广泛的影响是生物发光工具的开发，这些工具可以应用于药物发现和优化，特别是用于动物的非侵入性成像。迄今为止，生物发光成像在制药工业中由于光透射率差和酶不稳定性而受到限制。基础研究为生物发光成像的进步做出了贡献。我们的目标是弥合差距，扩大生物发光报告的使用。具体来说，除了细胞培养的细胞外，拟议的技术将使用生物传感器在实验室动物中快速评估候选药物。该技术可能对中枢神经系统（CNS）药物开发产生重大影响，并加速脑恶性肿瘤药物的优化。这一工具可能会导致更好的血脑屏障（BBB）通透性和更好的活性在大脑中的改进化合物，同时也防止了在人类志愿者和患者中测试次优化合物。这个I-Corps项目是基于开发新的药物筛选平台，使非侵入性检测药物活性和有效性在活体动物。最近，生物发光报告已被设计成更亮和红移，从而允许生物事件的深层组织成像。这些分子工具能够以无标记、非侵入性和途径特异性的方法检测药物活性。此外，这些生物传感器可用于监测活体动物中的药物活性，从而规避终端分析的许多限制。通过在体内评价靶向候选药物，无需终止，可以更准确地评价化合物的性能和功效。这对于优化穿透中枢神经系统（CNS）的分子特别有价值，其中血脑屏障（BBB）在CNS药物开发中提出了重大挑战。该项目的目标是确定这些生物传感器可以促进CNS化合物的快速评估的方式，以及这些工具何时可能在药物开发管道中产生最大的影响。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知识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 I-Corps program is the development of bioluminescence tools that may be applied to drug discovery and optimization, particularly for the non-invasive imaging of animals. To date, bioluminescence imaging in the pharmaceutical industry has been limited due to poor light penetrance and enzyme instability. Fundamental research has contributed to the advancement of bioluminescence imaging. The goal is to bridge the gap and expand the use of bioluminescent reporters. Specifically, the proposed technology will use biosensors for rapidly evaluating drug candidates in laboratory animals, in addition to cell cultured cells. This technology may have a significant impact on central nervous system (CNS) drug development and accelerate the optimization of drugs for brain malignancies. This tool may lead to improved compounds with better blood brain barrier (BBB) penetrance and better activity in the brain, while also preventing the testing of suboptimal compounds in human volunteers and patients.This I-Corps project is based on the development of new drug screening platforms that enable non-invasive detection of drug activity and efficacy in living animals. Recently, bioluminescent reporters have been engineered to be brighter and red-shifted, thereby allowing deep tissue imaging of biological events. These molecular tools enable the detection of drug activity in an approach that is label-free, non-invasive, and pathway-specific. In addition, these biosensors may be used to monitor drug activity in living animals, thus circumventing the numerous limitations of terminal analyses. By evaluating targeted drug candidates in vivo, without termination, the performance and efficacy of the compounds can be more accurately appraised. This is especially valuable for optimizing molecules penetrating the central nervous system (CNS), in which the blood-brain barrier (BBB) has presented significant challenges in CNS drug development. The goal of this project is to determine the ways in which these biosensors could facilitate the rapid assessment of CNS compounds, and when these tools may have the most impact in the drug development pipeline.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.