Mice Harboring Human DISC1-Boymaw Fusion Transcripts

描述（由申请人提供）：精神分裂症是普通人群中的常见病，患病率为1%。三个关于家庭聚集、同卵双胞胎和收养儿童的经典遗传研究表明，精神分裂症的病因有很强的遗传贡献。在最近的人类连锁和遗传关联研究中，已经确定了几个候选易感基因。然而，所有候选基因携带的疾病风险比都很低，而且很少发现功能性突变。因此，很难在转基因小鼠模型中研究基因突变如何促进精神分裂症的发病机制。然而，在精神分裂症家族中，有一些明确的功能性突变被确定为高外显率。对这些已知功能突变基因的研究将为我们理解精神分裂症的潜在分子机制提供有价值的见解。精神分裂症紊乱（DISC1）在一个苏格兰精神分裂症大家族中被鉴定出来，构成了一个清晰而引人注目的高外显率功能突变。我们最近的研究表明，在苏格兰精神分裂症家族中，另一个基因Boymaw也被破坏，并且在DISC1和Boymaw基因之间形成了两个融合转录本。我们假设这些融合转录本在与精神分裂症相关的神经回路中产生嵌合蛋白。为了验证我们的假设，我们建议创建一个表达DISC1-Boymaw融合转录本的人源化小鼠系。成功开发表达DISC1-Boymaw转录本的条件敲入小鼠系，不仅对研究疾病的分子机制，而且对探索通过纠正基因突变来预防和治疗行为异常（诱导性Cre-LoxP系统）具有重要意义。这样的小鼠也可以用来检查遗传易感性（融合转录物）和与精神分裂症和其他神经精神疾病相关的环境损害之间的关系，如压力、免疫挑战、发育损害或表观遗传效应。这些小鼠将在理解易感基因在何处以及如何影响特定神经基质参与调节精神相关的内表型方面发挥关键作用。为了启动这一假设的调查，提出了以下具体目标。R21期特异性目的特异性目的1：产生携带人DISC1-Boymaw融合转录物的人源化小鼠。目的1：验证DISC1-Boymaw融合转录物的表达导致海马发育异常的假设。具体目的2：验证DISC1-Boymaw融合转录本的表达在精神分裂症相关行为中产生功能损伤的假设。公共卫生相关性：人类DISC1基因被认为是精神分裂症最引人注目的易感基因之一，精神分裂症是一种慢性、严重的精神障碍，对患者、其家庭和社区的生活质量造成了沉重的经济负担。最近，另一个与DISC1突变有关的基因Boymaw基因被发现与DISC1基因形成融合转录本。了解这些融合转录物的作用将有助于阐明精神分裂症发病机制的分子和神经通路，以及提高诊断和指导开发副作用最小的有效药物治疗。

DESCRIPTION (provided by applicant): Schizophrenia is a common disease in the general population with 1% prevalence. Three classic genetic studies on family aggregation, monozygotic twins, and adopted children revealed that there is a strong genetic contribution to the etiology of schizophrenia. Several candidate susceptibility genes have been identified in the recent human linkage and genetic association studies. All candidate genes carry low risk ratios for the disease however, and few functional mutations have been identified. Therefore, it is difficult to study how the genetic mutation would contribute to the pathogenesis of schizophrenia in transgenic mouse models. However, there are a few well defined functional mutations identified with high penetrance in schizophrenia families. The studies on these genes with known functional mutations will provide valuable insights for our understanding of the underlying molecular mechanism for schizophrenia. Disrupted-in-schizophrenia (DISC1) was identified in a large Scottish schizophrenia family and constitutes a clear and compelling functional mutation with high penetrance. Our recent studies demonstrated that another gene, Boymaw, was also disrupted in the Scottish schizophrenia family and two fusion transcripts were formed between DISC1 and Boymaw genes. We hypothesize that these fusion transcripts give rise to chimeric proteins in neural circuitry relevant to schizophrenia. To test our hypothesis, we propose to create a humanized mouse line expressing both DISC1-Boymaw fusion transcripts. The successful development of a conditional knockin mouse line expressing both DISC1-Boymaw transcripts will be invaluable not only to study the molecular mechanism for the disease but also to explore both prevention and cure of behavioral abnormalities by correcting the genetic mutations (inducible Cre-LoxP system). Such mice can also be used to examine relationships between genetic vulnerability (fusion transcripts) and environmental insults relevant to schizophrenia and other neuropsychiatric disorders, such as stress, immune challenge, developmental insult, or epigenetic effects. These mice will play a crucial role in understanding where and how susceptibility genes affect specific neural substrates involved in the modulation of psychiatric-related endophenotypes. To initiate the investigation of this hypothesis, the following specific aims are proposed. R21 PHASE SPECIFIC AIMS Specific Aim 1: Generation of humanized mice harboring human DISC1-Boymaw fusion transcripts. R33 PHASE SPECIFIC AIMS Specific Aim 1: To test the hypothesis that expression of the DISC1-Boymaw fusion transcripts results in abnormal hippocampal development. Specific Aim 2: To test the hypothesis that expression of DISC1-Boymaw fusion transcripts produces functional impairments in schizophrenia-relevant behaviors. PUBLIC HEALTH RELEVANCE: The human DISC1 gene has been proposed to be one of the most compelling susceptibility genes for schizophrenia, a chronic, severe mental disorder imposing a high financial burden on the quality of life of the patients, their families and communities. Recently, the Boymaw gene, another gene involved in the DISC1 mutation, has been identified to form fusion transcripts with the DISC1 gene. Understanding of the effects of these fusion transcripts will help elucidate the molecular and neural pathways for the pathogenesis of schizophrenia, as well as improve diagnosis and guide the development of effective drug treatment with minimal side effects.