Mouse models of ZNF804A

 描述（由申请人提供）：本提案将研究Zfp804a在小鼠大脑发育和行为中的作用，作为精神疾病生物学基础的潜在模型。精神分裂症和其他精神疾病几十年来一直被认为具有家族性成分，但这些疾病背后的基因直到最近才开始被确定。除了极少数在罕见家族中具有高变异率的基因外，联盟研究已经开始以高置信度鉴定大量基因，其常见变异与一般人群中的精神分裂症和双相情感障碍相关。虽然这些相关的变异个体对诊断的预测能力有限，但它们仍然标志着这种疾病的生物学基础。因此，了解这些基因影响大脑和精神功能的基本机制可能为风险和干预提供关键见解。与精神分裂症和双相情感障碍相关性最好的支持和最重复的是ZNF 804A，它编码一种具有单一锌指基序和其他功能未知的保守序列的蛋白质。这项探索性的提议旨在建立动物模型，以（1）测试小鼠中的ZNF 804A同系物是否是大脑发育或正常行为所必需的，（2）促进分子研究，将ZNF 804A置于细胞和分子背景下。

 DESCRIPTION (provided by applicant): This proposal will examine the role of Zfp804a in mouse brain development and behavior as a potential model for biological basis of psychiatric illness. Schizophrenia and other psychiatric illnesses have been recognized to have a familial component for several decades, but genes that underlie these disorders have only recently begun to be identified. In addition to a very few genes with high penetrance in rare families, consortium studies have begun to identify with high confidence larger numbers of genes whose common variants are associated with schizophrenia and bipolar disorder in the general population. While these associated variants individually have only limited predictive power for diagnosis, they nonetheless mark biological bases for the disorder. Understanding the basic mechanisms through which these genes impact brain and mental function may therefore provide key insights into risk and intervention. One of the best-supported and most-replicated associations with schizophrenia and bipolar disorder is ZNF804A, which encodes a protein with a single zinc finger motif and other conserved sequences whose functions are not known. This exploratory proposal aims to create animal models that will (1) test whether the ZNF804A homolog in mouse is required for brain development or normal behavior and (2) facilitate molecular studies to place ZNF804A in cellular and molecular context.