The UCLA Center for Medical Countermeasures Against Radiation

 描述(由申请人提供)：尽管对辐射对正常组织的影响进行了广泛的调查，但由于恐怖主义行动可能导致的辐射暴露，目前缺乏减轻辐射暴露的试剂。我们已经为发现和开发新型缓释剂开发了一个有效的基础设施。结果是一个由大约30种药物组成的组合，可以显著减轻小鼠模型中的急性辐射综合征(ARS)，至少有一种药物有效对抗晚期效应。未来5年将致力于确定和优化缓释剂的优先顺序，并确定目标和生物标记物，使其能够合理使用，无论是单独还是在 组合。我们的核心以极大的灵活性迎接了我们不断发展的计划的挑战。他们将产品从高通量筛选(HTS)、化学信息学、合成、药物优化、药代动力学和动物试验，到专利和许可。为了承认它们不断演变的角色，我们将它们重新命名为产品开发核心(PDC)和产品测试动物核心(PTAC)。他们将保留其在药物发现方面的许多职能，但将重新定位为更先进的产品开发。PDC将执行化学聚集和毒物信息学，以优化产品开发。它将把它的输出与我们的灵知生物PTAC整合在一起，该PTAC拥有高度可重复性的ARS模型和一个大型延迟效应(DEARE)计划。药物发现将在很大程度上是一项核心活动，通过执行委员会的行动与项目相结合，执行委员会将优先开发产品。项目将在组织损伤的情况下研究缓释剂，以通过目标识别促进其合理使用。项目1将使用减肥剂重新平衡免疫反应，这些免疫反应不仅对从ARS中营救至关重要，而且对预防DeARE也是至关重要的。它的兴趣与项目2密切相关，该项目研究全身照射(WBI)后出现的一种新的髓系细胞亚群。我们的一种主要缓释剂可以增强这种反应，并且绝对需要这些细胞来活动，FDA批准的缓释剂G-CSF可能就是这样的情况。他们对DeARE的贡献，特别是对心肌病的贡献也将被调查。项目3的重点是通过内皮细胞释放的因子恢复造血干细胞的生态位，此前内皮细胞证明了多核营养素可以缓解HARs。在这次更新中，他们使用遗传和药理学模型来研究蛋白酪氨酸磷酸酶受体Sigma是否调节对WBI的造血反应。项目4基于这样一个事实，即我们的一种先导化合物通过Wnt途径刺激肠道和中枢神经干细胞的能力，从而减轻肠道辐射损伤。这些项目之间的整合程度很高，因为我们寻求更深入地了解WBI后组织损伤、先天免疫反应和干细胞恢复过程之间的相互作用，并利用这些过程来缓解ARS和DEARE。核心参与到每个项目中，并帮助推动重复、优化和优先的产品开发流程。

 DESCRIPTION (provided by applicant): Despite extensive investigations into the effects of radiation on normal tissues, there is a dearth of agents for mitigating radiation exposure as might occur as a result of terrorist action. We have developed an effective infrastructure for the discovery and development of novel mitigators. The result is a portfolio of about 30 agents that can significantly mitigate acute radiation syndrome (ARS) in murine models, with at least one active against late effect. The next 5 years will be dedicated to prioritizing and optimizing mitigators and identifying targets and biomarkers that will allow their rational use, singly and in combination. Our Cores have met the challenges of our evolving Program with great flexibility. They have taken products through high throughput screening (HTS), chemoinformatics, synthesis, drug optimization, pharmacokinetics, and animal testing, to patenting and licensing. In acknowledgement of their evolving roles, we have renamed them the Product Development Core (PDC) and Product Testing Animal Core (PTAC). They will retain many of their functions in drug discovery, but will reposition themselves towards more advanced product development. The PDC will perform chemical clustering and toxicoinformatics so as to optimize product development. It will integrate its output with our gnotobiotic PTAC that has highly reproducible models of ARS and a large delayed effects (DEARE) program. Drug discovery will be largely a Core activity that is integrated with projects through the actions of an Executive Committee who will prioritize products for development. Projects will study mitigators within contexts of tissue damage that will promote their rational use through target identification. Project 1 will use mitigators to rebalance immune responses that are critical not only for rescue from ARS but also for preventing DEARE. Its interests are closely allied with those of Project 2 that examines a novel subpopulation of myeloid cells that arises after whole body irradiation (WBI). One of our lead mitigators boosts this response and absolutely requires these cells for activity, as may the case for FDA-approved mitigator G- CSF. Their contribution to DEARE and especially cardiomyopathy will also be investigated. Project 3 focuses on restoration of the hematopoietic stem cell niche by factors released by endothelial cells, following their demonstration that pleiotrophin can mitigate hARS. In this renewal they use genetic and pharmacological models to investigate whether protein tyrosine phosphatase receptor sigma modulates the hematopoietic response to WBI. Project 4 builds on the fact that one of our lead compounds mitigates gut radiation damage by looking at its ability to stimulate gut and CNS stem cells through the Wnt pathway. The level of integration between the projects is high as we seek to obtain a deeper understanding of the interactions between tissue damage, innate immune responses, and stem cell recovery processes after WBI and to exploit these to mitigate ARS and DEARE. The Cores are involved in every project and help drive a reiterative, optimized, and prioritized product development process.