Mice Harboring Human DISC1-Boymaw Fusion Transcripts

携带人类 DISC1-Boymaw 融合转录本的小鼠

• 批准号: 7647677
• 负责人: XIANJIN ZHOU
• 金额: $ 15.45万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-02 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7647677
• 关键词: Adverse effects; Affect; Animals; Attention; Behavior; Behavioral; Candidate Disease Gene; Charge; Chimeric Proteins; Chromosomal translocation; Chronic; Clinical; Cognitive; Communities; Complex; Core Facility; Development; Diagnosis; Disease; Emotional; Epigenetic Process; Etiology; Exhibits; Family; Funding; Future; Gene Mutation; General Population; Generations; Genes; Genetic; Genetic Predisposition to Disease; Hippocampus (Brain); Human; Immune; Investigation; Laboratories; Magnetic Resonance Imaging; Measures; Mental Health; Mental disorders; Modeling; Molecular; Monozygotic Twinning; Monozygotic twins; Mus; Mutant Strains Mice; Mutation; Neural Pathways; Neurosciences Research; Odds Ratio; Odors; Pathogenesis; Patients; Penetrance; Pharmaceutical Preparations; Phase; Phenotype; Play; Predisposition; Prevalence; Prevention; Process; Quality of life; Research Institute; Role; Schizophrenia; Series; Short-Term Memory; Stress; Susceptibility Gene; Symptoms; System; Testing; Transcript; Transgenic Mice; United States National Institutes of Health; Validation; adopted child; endophenotype; functional disability; genetic association; improved; information processing; insight; mouse model; neural circuit; neuropsychiatry; prepulse inhibition; public health relevance; relating to nervous system; tool; trait

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.

描述（由申请人提供）：精神分裂症是一般人群中的常见疾病，患病率为1%。三个经典的遗传学研究家庭聚集，单卵双胞胎，并通过儿童揭示了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，所有候选基因都携带低风险比率的疾病，并且很少有功能性突变被发现。因此，很难在转基因小鼠模型中研究基因突变如何导致精神分裂症的发病。然而，在精神分裂症家族中有一些明确的功能突变被鉴定为高突变率。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分子机制提供有价值的见解。在一个大型苏格兰精神分裂症家族中发现了精神分裂症中的分裂症（DISC 1），并构成了一个清晰而引人注目的功能突变，具有高突变率。我们最近的研究表明，苏格兰精神分裂症家族中的另一个基因Boymaw也被破坏，并且DISC 1和Boymaw基因之间形成了两个融合转录本。我们推测，这些融合转录物引起嵌合蛋白在神经回路相关的精神分裂症。为了验证我们的假设，我们建议建立一个人源化的小鼠系表达两个DISC 1-Boymaw融合转录。成功开发表达DISC 1-Boymaw转录本的条件性敲入小鼠品系不仅对于研究疾病的分子机制，而且对于探索通过纠正基因突变（诱导型Cre-LoxP系统）预防和治疗行为异常都是非常宝贵的。这些小鼠也可用于检查遗传脆弱性（融合转录物）和与精神分裂症和其他神经精神障碍相关的环境损伤（如应激、免疫挑战、发育损伤或表观遗传效应）之间的关系。这些小鼠将在了解易感基因在哪里以及如何影响参与精神病相关内表型调节的特定神经基质方面发挥至关重要的作用。为了启动对这一假设的调查，提出了以下具体目标。R21阶段特异性目的特异性目的1：产生携带人DISC 1-Boymaw融合转录物的人源化小鼠。R33阶段特异性目的特异性目的1：检验DISC 1-Boymaw融合转录物的表达导致海马发育异常的假设。具体目标二：检验DISC 1-Boymaw融合转录本的表达在精神分裂症相关行为中产生功能障碍的假设。公共卫生关系：人类DISC 1基因已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精神障碍，对患者及其家庭和社区的生活质量造成了沉重的经济负担。最近，Boymaw基因，另一个参与DISC 1突变的基因，已被鉴定为与DISC 1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，以及改善诊断和指导开发副作用最小的有效药物治疗。