HUMAN CHRNA7 MODELS IN MICE

小鼠体内的人类 CHRNA7 模型

• 批准号: 8120339
• 负责人: ROBERT R FREEDMAN
• 金额: $ 26.94万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8120339
• 关键词: Alleles; Animal Model; Animals; Auditory; Brain; Cells; Choline; Clinical Research; Clinical Trials; Development; Fetal Development; Functional disorder; GABA transporter; Genes; Genetic; Genetic Variation; Glutamates; Haplotypes; Hippocampus (Brain); Homo; Human; Impaired cognition; Infant Development; Instruction; Intervention; Link; Modeling; Mouse Strains; Mus; Mutation; Nicotinic Agonists; Nicotinic Receptors; Nutrient; Pattern; Perinatal; Pharmaceutical Preparations; Phenotype; Point Mutation; Preventive; Production; Psychotic Disorders; Publications; Receptor Gene; Recording of previous events; Research; Role; Schizophrenia; Shapes; Stem cells; Supplementation; Symptoms; Techniques; Transgenic Mice; Translating; Variant; base; design; genetic resource; high risk; homologous recombination; immune activation; improved; mature animal; mouse model; neuron development; new therapeutic target; novel therapeutics; nucleus reticularis; perinatal intervention; prevent; receptor; research study; sensory gating

The mouse models of alpha? nicotinic receptor dysfunction of Project 4 have led to significant understanding of the role of allelic variants in the gene for this receptor in development and function of the hippocampus, particulary in regard to its role in auditory sensory gating; the possible therapeutiuc effects of nicotinic agonists on sensory gating dysfunction in schizophrenia; and the possible preventive effect of perinatal intervention with choline supplementation. As the discoveries of Project 4 are translated into clinical studies by Projects 1 and 2, possible limitations reflecting the differences between human CHRNA? and mouse Chrna? must be considered. Therfore Project 5 will attempt to produce a mouse that has the human CHRNA? in place of the mouse gene, using homologous recombination in mouse embyonic stem cells. This technique will allow us to study differences between the mouse and human gene in Experiment 1, to assess the effects of variants in the gene found in schizophrenia by Project 3 in Experiment 2, and to determine the effect of choline on the development of neurons that have human versions of CHRNA? and the alpha 7 nicotinic receptor in Experiment 3 to help Project 2 design the safest and most effective human treatment. Although production of a transgenic mouse is always a high risk project, the Center's history of successful translational use of research findings in animal models to shape clinical trials now supports this enhancement of its animal model of the genetic basis of a? nicotinic receptor dysfunction. Project 5 supports clinical research in Projects 1 and 2 and receives genetic resources frim Project 3, phenotyping support from Project 4, and will interact with Project 6 to examine effects of maternal immune activation. RELEVANCE (See instructions): New therapeutic strageties for schizophrenia are needed to improve cognitive dysfunction and negative symptoms and to prevent the development of psychosis. The Center examines a dysfunctioning nicotinic acetylcholine receptor as a new therapeutic target. It investigates a new drug treatment for schizophrenia and a preventative nutrient intervention during early infant development, both of which activate this receptor.

alpha的鼠标模型？项目4的烟碱受体功能障碍已导致大量了解 等位基因变体在基因中的作用，用于该受体在海马的发育和功能中的作用， 特别是其在听觉感觉门控的作用；烟碱可能的治疗作用 精神分裂症的感官传球功能障碍的激动剂；以及围产期的预防作用 补充胆碱的干预。由于项目4的发现被转化为临床研究 按项目1和2，可能的局限性反映了人类CHRNA之间的差异？和鼠标 chrna？必须考虑。因此，项目5将尝试生产具有人类的鼠标 chrna？使用小鼠embyonic干细胞中的同源重组代替小鼠基因。这 技术将使我们能够研究实验1中小鼠和人类基因之间的差异，以评估 通过实验2中的项目3在精神分裂症中发现的基因中变体的影响，并确定 胆碱对具有人体版本的CHRNA的神经元发展的影响？和alpha 7 实验3中的烟碱受体，以帮助项目2设计最安全，最有效的人类治疗。 尽管生产转基因鼠标始终是一个高风险项目，但中心的成功历史 现在，动物模型中研究结果的翻译使用以塑造临床试验，现在支持这一点 增强其动物模型的遗传基础？烟碱受体功能障碍。 项目5支持项目1和2中的临床研究，并接收遗传资源。 项目4的表型支持，并将与项目6相互作用以检查母体免疫的影响 激活。 相关性（请参阅说明）： 需要新的精神分裂症治疗性散乱，以改善认知功能障碍和负面 症状并防止精神病的发展。该中心检查功能障碍的烟碱 乙酰胆碱受体是一种新的治疗靶点。它研究了一种用于精神分裂症的新药物治疗 以及婴儿早期发育期间的预防营养干预，这两者都激活了该受体。