UAB Pilot Center for Precision Animal Modeling (C-PAM)

摘要（总体） 随着通过全基因组测序确定的潜在变异数量的迅速增加， 在罕见疾病患者中使用这种技术，遗传学家现在面临的挑战是确认这些变异 是造成这种表型的原因。这需要详细的评估和注释，以区分因果关系 与那些简单的非显著多态性和测序或作图错误不同。这是一 复杂的问题，以解决需要跨学科的方法，详细的生物信息学分析， 产生信息丰富的动物模型，并共同努力评估变异。实现这一目标 通常超出了单个实验室可以轻松或有效完成的任务。在这方面， 临床和转化科学与精准医学研究所组建了一个科学家团队， 临床医生在基础研究，计算和数据科学，人类遗传学，临床诊断， 和动物模型生成，形成了UAB精密动物建模中心（C-PAM）。该团队已经 建立了一个管道，其中研究和临床社区提名的变体将被彻底分析 使用C-PAM生物信息学部分生成的创新生物信息学工具包。选定的变体将 由C-PAM疾病建模单位在动物中建模，并评估用于人类疾病的新模型 C-PAM临床前/协同临床部分的临床医生的相关性。一旦生成，C-PAM建立协作 将利用详细的信息分析和动物资源，将通过C-PAM分配 资源及服务组，以加深我们对疾病发病机制的认识， 新的或再利用的治疗剂，并有助于改善人类健康。C-PAM将利用和组织 我们现有的专业知识，以实现我们的愿景，成为一个国家的资源，高效和具有成本效益 分析在罕见疾病患者中鉴定的基因变异的致病性， 动物模型来研究疾病机制和靶向治疗。

ABSTRACT (OVERALL) With the rapid increase in the number of potential variants being identified through whole genome sequencing technologies in patients with rare disorders, the challenge for geneticists is now to confirm that these variants are causative of the phenotype. This requires detailed assessment and annotation to separate the causative variant from those that are simple nonsignificant polymorphisms and sequencing or mapping errors. This is a complex problem to address requiring interdisciplinary approaches, detailed bioinformatic analysis, the generation of informative animal models, and a concerted effort to evaluate the variants. Accomplishing this goal is frequently beyond what an individual lab can easily or efficiently accomplish. In this regard, the Center for Clinical and Translational Science and the Precision Medicine Institute assembled a team of scientists and clinicians with expertise in basic research, computational and data sciences, human genetics, clinical diagnosis, and animal model generation to form the UAB Center for Precision Animal Modeling (C-PAM). The team has established a pipeline in which research and clinical community nominated variants will be thoroughly analyzed using an innovative bioinformatic toolkit generated by the C-PAM Bioinformatics Section. Selected variants will be modeled in animals by the C-PAM Disease Modeling Unit and the new models evaluated for human disease relevance by clinicians in the C-PAM Pre/Co-clinical Section. Once generated, C-PAM established collaborations will utilize the detailed informatic analyses and the animal resource that will be distributed through the C-PAM Resource and Services Section to advance our understanding of disease pathogenesis, to ascertain efficacy of novel or repurposed therapeutics, and to contribute to improved human health. C-PAM will leverage and organize our already existing expertise to fulfill our vision to become a national resource for efficient and cost-effective analysis of pathogenicity of gene variants identified in patients with rare disorders and to produce informative animal models to pursue disease mechanisms and targeted therapeutics.