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

I-Corps计划的更广泛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。到目前为止，由于透光性差和酶的不稳定性，生物发光成像在制药行业中的应用一直受到限制。基础研究为生物发光成像的发展做出了贡献。目标是弥合这一差距，扩大生物发光记者的使用。具体地说，除了细胞培养细胞外，这项拟议的技术还将使用生物传感器在实验室动物中快速评估候选药物。这项技术可能会对中枢神经系统(CNS)药物的开发产生重大影响，并加速脑部恶性肿瘤药物的优化。这一工具可能会导致改进的化合物具有更好的血脑屏障(BBB)渗透率和大脑中的更好活性，同时还可以防止在人类志愿者和患者身上测试次优化合物。这个i-Corps项目基于开发新的药物筛选平台，使药物活性和疗效能够在活体动物中进行非侵入性检测。最近，生物发光记者被设计成更明亮和红移，从而使生物事件的深层组织成像成为可能。这些分子工具能够以一种无标记、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的药物活性，从而绕过终端分析的众多限制。通过在体内评估靶向候选药物，而不需要终止，可以更准确地评估化合物的性能和疗效。这对于优化穿透中枢神经系统(CNS)的分子尤其有价值，因为在中枢神经系统(CNS)中，血脑屏障(BBB)是中枢神经系统药物开发中的重大挑战。该项目的目标是确定这些生物传感器如何促进CNS化合物的快速评估，以及这些工具何时可能在药物开发管道中产生最大影响。该奖项反映了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 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.