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

基本信息

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
项目类别：
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

项目摘要

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I阶段的SBIR应用中提出，通过在ES细胞中的同源重组中产生功能突变的丧失，以在小鼠中生成和销售小鼠人类精神疾病的遗传模型。所得小鼠菌株的纯合子和杂合动物都将在行为，药理，神经和神经内分泌水平上表征表征。特征的小鼠应变将提供给商业客户，以供铅药物评估筛查服务，也可以作为进一步的药物目标发现和表征项目的基材。在II阶段，我们将使用MWFS 1功能应变损失来进行体内验证，该化合物的基于细胞的高吞吐量筛选化合物，这些化合物能够在RNA水平上增加Wolframin的表达。已发表的人类链接数据和我们自己的实验室中小鼠产生的大量初步结果表明，WFS 1功能突变的丧失将对较高的认知功能产生深远的影响，而不会产生胚胎致死性。拟议项目的理性基于已发表的发现和我们自己的初步数据：1）。 Wolframin基因的突变是Wolfram综合征的因果，这是一种与少年发作糖尿病有关的进行性神经退行性疾病。 2）。精神病发生在大多数Wolfram综合征中发生，杂合携带者在其一生中患有重大精神疾病的可能性是26倍。 3）。在小鼠中，在几种既定的精神病模型中，以大脑特异性的方式对鼠WFSL的表达进行了动态调节，其中：a）MWFSL在孤立的小鼠的前额叶皮层中被下调，与在丰富的环境中饲养的小鼠相比，在富含小鼠中，wfsl在olfarty the Olfartery titber theber中均在the tumperighty the tumcleorder the tumcleore titber the tumcleore titber in Cormcle of the tumcle theber中。我们假设MWFS 1的功能丧失将在行为和神经系统水平上具有表型作用，这将使新的药物发现工作。但是，人类连锁研究，Wolfram综合征患者或携带者的人类病理生理学，也没有到目前为止收集的动物数据，都可以预测MWFS的精确行为表型1小鼠功能突变的丧失。我们尚不知道将建模哪种特定综合症的事实并不是该提案的责任。 Wolfram综合征是一种真正的人类疾病，显示出明显增强了对几种精神疾病的脆弱性。在该应用的第一阶段，我们仅寻求用于纯合和杂合WFS 1 K/O动物的行为和药理表征的资金。