Disease Modeling Unit

摘要 美国疾病控制与预防中心精准医学建模中心的疾病建模部门将负责制作 对中心的精密动物模型进行表型分析该股将使用先进的基因组编辑技术， 我们现有的动物建模项目开发的修饰技术和表型分析工作流程，以（1） 产生重现人类疾病相关变异的小鼠和苍蝇模型，以及（2）验证变异- 疾病关联，确定疾病机制，并在苍蝇和小鼠模型中测试假定的干预措施。 此外，该组亦会筛选恒河猕猴群落的基因排序数据，以确定哪些动物具有假定的 感兴趣基因中的疾病相关变异。该股将开展三个示范项目， 展示拟议中心对影响各种器官的未诊断和罕见疾病进行建模的能力 系统在不同的发病年龄，并将模式生物的发现转化回病人护理。这些 提名项目将整合苍蝇的机制研究与表型和干预研究， 小鼠，以证明苍蝇和小鼠模型的生产能力，表型分析能力的广度，以及 该中心生成的模型的潜在翻译影响。与生物信息学和 临床前/协同临床部分，该部门还将参与人类疾病相关变异体的提名 通过识别正确的精确动物模型（例如苍蝇、小鼠）和通过识别表型进行的过程 回答本地和外部提名者提出的临床相关问题的策略。该股还将 评估是否有一个推定的恒河猴模型可用于每个提名的变异。提名时 如果选定了用于建模的变量，该股将在项目期间与资源和服务科密切合作， 规划以确保选择正确的模型，并制定严格的研究计划。总的来说，目标 使用该单位的精确模型进行的研究将揭示新的疾病机制，揭示新的 疾病生物标志物和表型，并为患者确定潜在的新治疗策略。

ABSTRACT The Disease Modeling Unit of the BCM Center for Precision Medicine Modeling will be responsible for producing and phenotyping the Center’s precision animal models. The Unit will use advanced genome editing and modification techniques and phenotyping workflows developed by our existing animal modeling programs to (1) produce mouse and fly models that recapitulate human disease-associated variants and (2) validate variant- disease associations, identify disease mechanisms, and test putative interventions in fly and mouse models. Moreover, the Unit will screen sequencing data from rhesus macaque colonies to identify animals with putative disease-associated variants in genes of interest. The Unit will undertake three Demonstration Projects intended to showcase the proposed Center’s ability to model undiagnosed and rare diseases affecting a variety of organ systems at different ages of onset and to translate model organism findings back to patient care. These nomination projects will integrate mechanistic studies in the fly with phenotyping and intervention studies in the mouse to demonstrate the fly and mouse model production capacity, breadth of phenotyping capabilities, and potential translational impact of models generated by the Center. Together with the Bioinformatics and Preclinical/Co-Clinical Sections, the Unit will also participate in the human disease-associated variant nomination process by identifying the correct precision animal model (e.g. fly, mouse) and by identifying phenotyping strategies that answer clinically relevant questions posed by local and external nominators. The Unit will also assess whether a putative rhesus macaque model is available for each nominated variant. When nominated variants are selected for modeling, the Unit will work closely with the Resource and Service Section during project planning to ensure that the correct models are selected, and a rigorous study plan is enacted. Overall, the goal of studies performed using the Unit’s precision models will be to uncover new disease mechanisms, reveal new disease biomarkers and phenotypes, and identify potential new therapeutic strategies for patients.