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：
6584502
负责人：
Daniela Brunner
金额：
$ 23.51万
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 2005-02-28
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）：我们建议在此 I 期 SBIR 申请中通过同源基因在小鼠基因 Wolframin 1 (mWfsl) 中产生功能丧失突变，从而在小鼠中生成并销售人类精神疾病的遗传模型。 ES细胞中的重组。所得小鼠品系的纯合和杂合动物都将在行为、药理学、神经学和神经内分泌水平上进行表型表征。经过表征的小鼠品系将提供给商业客户，用于先导药物评估的筛选服务，并作为进一步药物靶点发现和表征项目的底物。在第二阶段，我们将使用 mWfs 1 功能丧失菌株对源自基于细胞的高通量化合物筛选的化合物进行体内验证，这些化合物能够在 RNA 水平上增加钨胺表达。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 功能丧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。拟议项目的合理性基于已发表的研究结果和我们自己的初步数据：1）。 Wolframin 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的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，杂合子携带者一生中患严重精神疾病的可能性是其 26 倍。 3）。在几种已建立的小鼠精神疾病模型中，小鼠 Wfsl 的表达以脑位点特异性方式动态调节，其中：a) 与在丰富环境中饲养的小鼠相比，隔离饲养的小鼠的前额皮质中 mWfsl 下调, b) 在 PCP 精神病模型中，Wfsl 在嗅结节中上调。我们假设 mWfs 1 功能的丧失将在行为和神经水平上产生表型效应，这将使新药物的发现工作成为可能。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，都无法预测小鼠中 mWfs 1 功能丧失突变的精确行为表型。事实上，我们还不知道将模拟哪种特定综合症，但这并不是该提案的责任。沃尔弗拉姆综合症是一种真正的人类疾病，它对多种形式的精神疾病的脆弱性显着增强。在本申请的第一阶段，我们仅为纯合和杂合 Wfs 1 k/o 动物的行为和药理学特征寻求资金。