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）：我们在该I期SBIR申请中提出，通过在ES细胞中同源重组在鼠基因Wolframin 1（mWfsl）中产生功能缺失突变，在小鼠中产生并销售人类精神疾病的遗传模型。所得小鼠品系的纯合和杂合动物将在行为、药理学、神经学和神经内分泌水平上进行表型表征。经鉴定的小鼠品系将提供给商业客户，用于先导药物评价的筛选服务，并作为进一步药物靶点发现和表征项目的底物。在第II阶段，我们将使用mWfs 1功能丧失菌株对衍生自基于细胞的化合物高通量筛选的化合物进行体内验证，所述化合物能够在RNA水平上增加钨蛋白表达。已发表的人类连锁数据和我们自己实验室在小鼠中产生的大量初步结果表明，Wfs 1功能缺失突变将对更高的认知功能产生深远的影响，而不会产生胚胎致死性。建议项目的理由是基于已发表的研究结果和我们自己的初步数据：1）。Wolfram基因突变是Wolfram综合征的病因，Wolfram综合征是一种与青少年发病糖尿病相关的进行性神经退行性疾病。2）。大多数Wolfram综合征病例都会出现精神疾病，杂合子携带者在其一生中出现重大精神疾病的可能性要高出26倍。3）。鼠Wfsl的表达在几种建立的小鼠精神病模型中以脑基因座特异性方式被动态调节，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皮质中mWfsl被下调，B）在精神病的PCP模型中，Wfsl在嗅结节中被上调。我们假设mWfs 1功能的丧失将在行为和神经水平上产生表型影响，这将使新药发现工作成为可能。然而，无论是人类连锁研究，Wolfram综合征患者或携带者的人类病理生理学，还是迄今为止收集的动物数据，都不能预测小鼠中mWfs 1功能丧失突变的精确行为表型。事实上，我们还不知道哪种特定的综合征将被建模，这不是这个建议的责任。Wolfram综合征是一种真正的人类疾病，它显示出对几种精神疾病的明显增强的脆弱性。在本申请的I期，我们仅寻求纯合和杂合Wfs 1 k/o动物的行为和药理学表征的资金。