HUMAN CHRNA7 MODELS IN MICE

小鼠体内的人类 CHRNA7 模型

基本信息

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
项目类别：
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

项目摘要

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.

阿尔法的鼠标模型？项目 4 的烟碱受体功能障碍引起了重要的理解该受体基因中的等位基因变异在海马发育和功能中的作用，特别是它在听觉感觉门控中的作用；烟碱可能的治疗作用精神分裂症感觉门控功能障碍的激动剂；以及围产期可能的预防作用补充胆碱进行干预。随着项目 4 的发现转化为临床研究通过项目 1 和 2，可能存在的局限性反映了人类 CHRNA 之间的差异？和鼠标科纳？必须考虑。因此，Project 5 将尝试生产一种具有人类特征的小鼠。 CHRNA？使用小鼠胚胎干细胞中的同源重组来代替小鼠基因。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，以评估项目 3 在实验 2 中发现的精神分裂症基因变异的影响，并确定胆碱对具有人类 CHRNA 的神经元发育有何影响？和阿尔法7 实验 3 中的烟碱受体可帮助项目 2 设计最安全、最有效的人类治疗方法。尽管转基因小鼠的生产始终是一个高风险项目，但该中心的成功历史动物模型研究结果的转化应用现在支持了这一点其动物模型的遗传基础有哪些？烟碱受体功能障碍。项目 5 支持项目 1 和 2 的临床研究，并接收项目 3 的遗传资源，来自项目 4 的表型分析支持，并将与项目 6 互动以检查母体免疫的影响激活。相关性（参见说明）：精神分裂症需要新的治疗策略来改善认知功能障碍和消极情绪症状并防止精神病的发展。该中心检查功能失调的烟碱乙酰胆碱受体作为新的治疗靶点。它研究了一种治疗精神分裂症的新药物以及婴儿早期发育期间的预防性营养干预，两者都会激活该受体。