Wolframin gene ablation in mice as a model for human men

小鼠中的 Wolframin 基因消融作为人类男性的模型

• 批准号: 6710124
• 负责人: Daniela Brunner
• 金额: $ 21.35万
• 依托单位: PSYCHOGENICS, INC.
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-03-01 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6710124
• 关键词: antidepressants; antipsychotic agents; behavior test; diabetes mellitus; drug screening /evaluation; gene expression; gene targeting; genetic models; genetically modified animals; hearing disorders; laboratory mouse; laboratory rat; mental disorder chemotherapy; model design /development; neuropharmacologic agent; optic nerve disorder; prefrontal lobe /cortex; psychopharmacology; psychotropic drugs; terminal nick end labeling

DESCRIPTION (provided by applicant): We propose in this phase I SBIR application to generate and market a genetic model for a human psychiatric disorder(s) in mice by generating a loss of function mutation in the murine gene Wolframin 1 (mWfsl) through homologous recombination in ES cells. Both, homozygous and heterozygous animals of the resulting mouse strain will be phenotypically characterized at the behavioral, pharmacological, neurological and neuro-endocrine level. The characterized mouse strain will be made available to commercial clients for both screening services for lead drug evaluation and as a substrate for further drug target discovery and characterization projects. In phase II we will use the mWfs 1 loss of function strain for the in vivo validation of compounds derived from a cell based high throughput screen for compounds, which are able to increase wolframin expression at the RNA level. Published human linkage data and a large amount of preliminary results generated in mouse from our own laboratories indicate that Wfs 1 loss of function mutations will have profound effects on higher cognitive functions without generating embryonic lethality. The rational for the proposed project is based on published findings and our own preliminary data: 1). Mutations in the Wolframin gene are causal to the Wolfram syndrome, a progressive neurodegenerative disorder associated with juvenile onset diabetes mellitus. 2). Psychiatric illness occurs in most cases of Wolfram syndrome and heterozygous carriers are 26 times more likely to present with a major mental illness during their lifetime. 3). Expression of murine Wfsl is dynamically regulated, in a brain locus specific manner, in several established models of psychiatric disease in mice where: a) mWfsl is down-regulated in the prefrontal cortex of mice reared in isolation as compared to mice reared in enriched environments, b) Wfsl is up-regulated in the olfactory tubercle in a PCP model of psychosis. We hypothesize that loss of function of mWfs 1 will have phenotypic effects at the behavioral and neurological level which will enable novel drug discovery efforts. However, neither the human linkage studies, the human pathophysiology of Wolfram syndrome patients or carriers, nor the animal data gathered so far, allow a prediction about the precise behavioral phenotype of mWfs 1 loss of function mutation in mice. The fact that we do not yet know which specific syndrome will be modeled is not a liability of this proposal. Wolfram syndrome is a bona fide human disease that shows markedly enhanced vulnerability to several forms of mental illness. In Phase I of this application we seek funding only for the behavioral and pharmacological characterization of homozygous and heterozygous Wfs 1 k/o animals.

描述(由申请人提供)：在此阶段，我们建议通过在ES细胞中进行同源重组，产生小鼠基因Wolframin 1(MWfs1)的功能缺失突变，从而在小鼠中建立和销售人类精神障碍(S)的遗传模型。由此产生的小鼠品系的纯合子和杂合子动物都将在行为、药理学、神经学和神经内分泌水平上表现出特征。这种特化的小鼠品系将向商业客户提供先导药物评估的筛查服务，并作为进一步药物靶标发现和表征项目的底物。在第二阶段，我们将使用MWFS 1功能丧失菌株在体内验证从基于细胞的高通量筛选获得的化合物，这些化合物能够在RNA水平上增加wolframin的表达。已发表的人类连锁数据和我们自己实验室在小鼠身上产生的大量初步结果表明，WFS 1功能突变的丢失将对高级认知功能产生深远影响，而不会产生胚胎死亡。建议项目的合理性是基于已发表的研究结果和我们自己的初步数据：1)。Wolframin基因的突变是Wolfram综合征的原因，Wolfram综合征是一种与青少年糖尿病相关的进行性神经退行性疾病。2)。精神疾病发生在大多数Wolfram综合征病例中，杂合子携带者在一生中出现重大精神疾病的可能性是普通人的26倍。3)。在几种已建立的小鼠精神疾病模型中，小鼠WFSL的表达是以大脑轨迹特有的方式动态调节的，其中：a)与在丰富环境中饲养的小鼠相比，在隔离饲养的小鼠的前额叶皮质中mWFSL下调，b)在PCP精神病模型中，WFSL在嗅结节中上调。我们假设，MWFS1功能的丧失将在行为和神经水平上产生表型效应，这将使新药发现工作成为可能。然而，无论是人类连锁研究，还是Wolfram综合征患者或携带者的人类病理生理学研究，以及迄今收集的动物数据，都不能预测小鼠MWFS 1功能缺失突变的确切行为表型。事实上，我们还不知道将对哪种特定的综合症进行建模，这并不是这项建议的责任。Wolfram综合征是一种真正的人类疾病，表现出对几种形式的精神疾病的易感性明显增强。在这项应用的第一阶段，我们只为纯合子和杂合子WFS1k/o动物的行为和药理学特征寻求资金。