Pre-Clinical Testing Core

临床前试验核心（PTC）项目总结 IU/JAX阿尔茨海默病精确模型中心的临床前测试核心（PTC）将建立 并利用预定的进行/不进行决策点验证临床前测试筛选策略管道， 在生物学和病理学方面的药代动力学、药效学生物标志物和功能评估 相关AD小鼠模型，允许对潜在治疗剂进行标准化和无偏倚的评估。 该核心由临床前成像、神经药理学和动物模型表征方面的专家领导， IU的神经成像中心和JAX的小鼠神经行为表型分析，体内成像， 生理学核心设施，并得到IU临床药理学分析核心的支持。管道是主要的 和二次筛选集中于产生药代动力学（PK）和药效学（PD）生物标志物 在两个新一代AD小鼠模型中进行了结构效度评估。只有测试化合物， 证明生物标志物筛选中的靶点参与将转移到体内症状的三级筛选 修饰作用和确定新化合物的治疗窗。的具体目标 PTC是（1）建立一个标准化的测试管道，开发分析方案， 方法，创建数据存储库和反向翻译临床化合物失败;（2）验证 目前在两种生物学和病理学相关动物中进行临床试验的两种化合物的管道 （3）通过管道对新的测试化合物进行评估，这使得研究人员能够在 更大的AD研究社区，前所未有地获得经过验证的管道，标准化测试 方案和资源来筛选感兴趣的化合物。

PROJECT SUMMARY PRECLINICAL TESTING CORE (PTC) The Preclinical Testing Core (PTC) of the IU/JAX Alzheimer’s Disease Precision Models Center will establish and validate a preclinical testing screening strategy pipeline with predetermined go/no-go decision points using pharmacokinetics, pharmacodynamic biomarkers and functional assessments in biologically and pathologically relevant AD mouse models that allow standardized and unbiased assessments of potential therapeutic agents. The Core is led by experts in preclinical imaging, neuropharmacology, and animal model characterization at IU’s Center for Neuroimaging and JAX’s Mouse Neurobehavioral Phenotyping, In Vivo Imaging, and Physiology Core facilities, and supported by IU’s Clinical Pharmacology Analytical Core. The pipeline’s primary and secondary screens focus on generating pharmacokinetic (PK) and pharmacodynamic (PD) biomarker assessments in two new generation AD mouse models with construct validity. Only test compounds that demonstrate target engagement in the biomarker screens will move to tertiary screening for in vivo symptom modifying effects and determination of the novel compound’s therapeutic window. The specific aims of the PTC are (1) the establishment of a standardized testing pipeline, the development of the assay protocols and methods, the creation of the data repository and back-translating clinical compound failures; (2) validating the pipeline with two compounds currently in clinical trials in two biologically and pathologically relevant animal models; (3) the evaluation of novel test compounds through the pipeline which allows investigators in the greater AD research community with unprecedented access to a validated pipeline, standardized testing protocols, and resources to screen compounds of interest.