Mice Harboring Human DISC1-Boymaw Fusion Transcripts

携带人类 DISC1-Boymaw 融合转录本的小鼠

基本信息

批准号：
7851311
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
项目类别：
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/7851311
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

项目摘要

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）：精神分裂症是普通人群中的一种常见疾病，患病率为1％。关于家庭聚集，单卵双胞胎和收养儿童的三项经典遗传研究表明，对精神分裂症的病因有很大的遗传贡献。在最近的人类联系和遗传关联研究中已经鉴定出了几种候选敏感性基因。然而，所有候选基因的风险比率都低，但几乎没有发现功能突变。因此，很难研究转基因小鼠模型中精神分裂症的发病机理如何促进遗传突变。但是，精神分裂症家族中有一些明确定义的功能突变。对这些具有已知功能突变的基因的研究将为我们理解精神分裂症的基本分子机制提供宝贵的见解。在大型苏格兰精神分裂症家族中鉴定出了干扰性的雪橇症（DISC1），并构成具有高渗透率的清晰而引人注目的功能突变。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也被破坏了，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物在与精神分裂症有关的神经回路中产生嵌合蛋白。为了检验我们的假设，我们建议创建一个表达盘状木融合转录本的人性化小鼠系。表达两种盘的有条件的敲门蛋白小鼠系的成功发展不仅是研究该疾病的分子机制，而且还可以通过纠正遗传突变（可诱导的CRE-LOXP系统）来探索预防和治愈行为异常。此类小鼠还可以用于检查遗传脆弱性（融合转录本）与与精神分裂症和其他神经精神疾病有关的环境侮辱之间的关系，例如压力，免疫挑战，发育型损伤或表观遗传效应。这些小鼠将在理解易感性基因在何处以及如何影响参与精神病相关末端型调节的特定神经底物的何处以及如何影响基因中发挥关键作用。为了启动该假设的研究，提出了以下特定目标。 R21阶段特定目标特定目的1：具有人盘1-Boymaw融合笔录的人源性小鼠的产生。 R33阶段特异性目的特定目的1：检验盘状融合转录本的表达导致海马发育异常的假设。特定目的2：检验以下假设：盘状融合转录本的表达会导致与精神分裂症相关的行为产生功能障碍。公共卫生相关性：已提议人类Disc1基因是精神分裂症最引人注目的易感基因之一，这是一种慢性，严重的精神疾病，对患者，家人和社区的生活质量施加了很大的经济负担。最近，已经鉴定出与Disc1基因形成融合转录本的Boymaw Gene是另一个参与DISC1突变的基因。了解这些融合转录本的作用将有助于阐明精神分裂症发病机理的分子和神经途径，并改善诊断并指导有效的药物治疗，并以最小的副作用。