Pre-Clinical Testing Core

项目摘要临床前试验核心(PTC) IU/JAX阿尔茨海默病精确模型中心临床前测试核心(PTC)将建立 以及验证具有预定通过/不通过决策点的临床前测试筛选策略流水线 生物病理学中的药代动力学、药效生物标志物和功能评价 相关的AD小鼠模型，允许对潜在的治疗剂进行标准化和公正的评估。 Core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，网址为 印第安纳大学神经成像中心和JAX的小鼠神经行为表型，活体成像，以及 生理学核心设施，并得到印第安纳大学临床药理分析核心的支持。这条管道的主要 二次筛查侧重于产生药代动力学(PK)和药效学(PD)生物标志物 两种新一代AD小鼠模型的结构效度评估。仅测试符合以下条件的化合物 展示生物标记物筛查的目标参与度将转移到体内症状的第三级筛查 新化合物的修饰作用及治疗窗的确定。《公约》的具体目标 PTC是(1)建立标准化的检测管道，制定检测方案和 方法：建立数据库，回译临床用药失败；(2)验证 目前正在对两种生物和病理相关动物进行临床试验的两种化合物的管道 模型；(3)通过管道对新的测试化合物进行评估，使研究人员能够在 更大的AD研究社区，史无前例地访问经过验证的管道、标准化测试 协议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.