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.

阿尔法的老鼠模型？项目4的烟碱受体功能障碍导致了对 该受体基因的等位基因变体在海马体发育和功能中的作用， 特别是在听觉感觉门控方面的作用;尼古丁的可能治疗作用 激动剂对精神分裂症感觉门控功能障碍的影响及围产期应用激动剂的可能预防作用 补充胆碱的干预措施。随着项目4的发现转化为临床研究， 通过项目1和2，可能的限制，反映人类CHRNA之间的差异？和鼠标 Chrna？必须加以考虑。因此，项目5将试图生产一种具有人类的小鼠， CHRNA？在小鼠胚胎干细胞中使用同源重组来代替小鼠基因。这 这项技术将使我们能够在实验1中研究小鼠和人类基因之间的差异， 实验2中项目3在精神分裂症中发现的基因变异的影响，并确定 胆碱对具有人类CHRNA的神经元发育的影响？阿尔法7 实验3中的烟碱受体，以帮助项目2设计最安全和最有效的人类治疗。 虽然转基因小鼠的生产一直是一个高风险的项目，该中心的成功历史， 将动物模型中的研究结果转化为临床试验的结果，现在支持了这一点 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和项目2的临床研究，并从项目3获得遗传资源， 表型支持项目4，并将与项目6相互作用，以检查母体免疫的影响， activation. 相关性（参见说明）： 精神分裂症需要新的治疗策略，以改善认知功能障碍和阴性反应， 症状并预防精神病的发展。该中心检查了一个功能失调的尼古丁 乙酰胆碱受体作为新的治疗靶点。它研究一种治疗精神分裂症的新药 以及在婴儿早期发育期间的预防性营养干预，这两者都激活了这种受体。