De-risking PWS drug development through preclinical screening

Prader-Willi综合征(PWS)是一种遗传性神经发育障碍，个体表现出行为和精神问题。它是由于一些正常的父系表达的印记基因的缺失或异常的表观遗传调节而导致的。与Prader-Willi研究临床前动物网络基金会(FPWR-PCAN)合作，该项目的目标是表征新的PWS小鼠模型并标准化候选药物的临床前筛选平台[1]。我们将使用我们实验室建立的一些行为范式来评估PWS的两个小鼠模型的活动、感觉-运动门控、学习和记忆以及其他认知方面[2-4]。具体地说，现有的SNORD116-Ko小鼠模型[5，6]和新产生的IPW-Ko模型。此外，我们将使用新的IPW-KO小鼠进行一些分子分析，基于先前观察到的这种非编码RNA与包含非规范Notch配体DIk1[7]的单独印迹基因簇的调节作用。这两个模型的平行特征将使我们能够描绘出每个基因对整个PWS表型的相对贡献，从而有助于靶向治疗的发展。

Prader-Willi syndrome (PWS) is a genetic neurodevelopmental disorder in which individuals display behavioural and psychiatric problems. It is caused by loss of expression, either through deletion or abnormal epigenetic regulation, of a number of normally paternally expressed imprinted genes. Working with the Foundation for Prader-Willi Research Pre-clinical Animal Network (FPWR-PCAN), the aim of this project is characterise new PWS mouse models & standardise a pre-clinical screening platform for drug candidates [1]. We will use a number of behavioural paradigms established in our lab to assess activity, sensory-motor gating, learning and memory, and other aspects of cognition in two mouse models for PWS [2-4]. Specifically, an existing Snord116-ko mouse model [5,6] and a newly generated Ipw-ko model. In addition, we will be performing some molecular analyses using the novel Ipw-ko mouse, based on previous observations of interactions of this non-coding RNA with the regulation of a separate cluster of imprinted genes containing the non canoncial Notch-ligand, DIk1 [7]. Parallel characterisation of these two models will allow us to delineate the relative contribution of each gene to the overall PWS phenotype and therefore aid the developmentof targeted therapeutics.