MOUSE MOLECULAR AND NEUROBIOLOGICAL MODELS

小鼠分子和神经生物学模型

基本信息

批准号：
8120338
负责人：
ROBERT R FREEDMAN
金额：
$ 31.23万
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/8120338
关键词：
3&apos Untranslated Regions Accounting Acute Address Adolescent Adult Affect Affinity Age Agonist Alleles Animals Antibodies Appearance Auditory Auditory Evoked Potentials Autopsy Binding Binding Sites Biological Biological Assay Birth Brain Buffers Bungarotoxins Cell Line Cell membrane Cells Choline Cholinergic Receptors Chronic Clinical Research Cognitive Collaborations Congenic Strain DBA/2 Mouse DNA DNA Binding Data Data Analyses Development Dose Drug Formulations Edetic Acid Electrophoresis Electrophoretic Mobility Shift Assay Electrophysiology (science)Embryo Etiology Evoked Potentials Exhibits Figs - dietary Film Firefly Luciferases Frequencies Functional Magnetic Resonance Imaging Gene Expression Gene Expression Microarray Analysis Genes Genetic Genetic Polymorphism Genetic Variation Genotype Glutamates Glycerol Haplotypes Hippocampus (Brain)Histones Human Immunoglobulin G Impaired cognition Implant In Vitro Inbred C3H Mice Incubated Infant Infant Development Infection Instruction Interneurons Intervention Ions Kainic Acid Receptors Kinetics Label Laboratories Lead Life Linear Regressions Link Luciferases MYB gene Measurement Measures Medial Mediating Memory Messenger RNA Methods Methylation Modeling Molecular Molecular Genetics Molecular Target Mouse Strains Mus Mutate N-Methylaspartate Neonatal Neurobiology Neurons Newborn Infant Nicotine Nicotinic Agonists Nicotinic Receptors Nuclear Nuclear Extract Nuclear Protein Nuclear Proteins Nutrient Oligonucleotides Ondansetron Parents Pattern Performance Perfusion Perinatal Persons Pharmaceutical Preparations Phenotype Physiologic pulse Physiology Plasmids Positioning Attribute Pregnancy Procedures Proteins Proto-Oncogene Proteins c-myb Psychotic Disorders Publishing Radial Rattus Recruitment Activity Relative (related person)Renilla Renilla Luciferases Reporter Genes Reporting Research Personnel Research Project Grants Rodent Role Saline Sampling Schizophrenia Sensory Short-Term Memory Single Nucleotide Polymorphism Site Small Interfering RNA Students Supplementation Sustained-Release Preparation Symptoms TNFRSF5 gene Tachyphylaxis Tail Techniques Testing Therapeutic Intervention Time Transcription Repressor/Corepressor Transfection Variant Work analog auditory stimulus base brain tissue cholinergic cholinergic synapse congenic critical period desensitization design expression vector follow-up frontal lobe gamma-Aminobutyric Acid genetic association genetic variant hippocampal pyramidal neuron implantation improved in vitro activity kainate kaspar membrane synthesis methyl group mutant neurobiological mechanism neuron development neuronal cell body neurotransmission new therapeutic target novel therapeutics offspring osmotic minipump paired stimuli patch clamp perinatal intervention polyacrylamide gels postnatal postsynaptic presynaptic prevent promoter receptor receptor binding receptor expression research study response sensory gating sex subcutaneous transcription factor transmission process vector vector control young adult

项目摘要

Data generated largely by investigators of this Conte Center application provide compelling evidence that the alpha 7 nicotinic acetylcholine receptor subunit is a potential target for therapeutic intervention in schizophrenia. These data include the observations that the expression of the alpha7 subunit is reduced in the hippocampus of schizophrenics (Project 1), genetic variants in CHRNA7, the gene that encodes the alpha7 subunit, are associated with schizophrenia and auditory sensory gating deficits (Project 3) and auditory gating deficits are common among schizophrenics and the selective alpha7 agonist DMXB-A improves gating deficits (Project 1). In addition, the alpha7 selective agonist choline has been shown to improve auditory gating in human infants when administered perinatally (Project 2). Strikingly similar data have been obtained in mice. For example, we have shown in mice that 1) auditory gating deficits are correlated with reduced alpha7 receptor expression, 2) genetic variability in Chrna7 is linked to reduced expression of alpha7 receptors and auditory gating deficits, 3) the alpha7 receptor selective agonist DMXB-A improves gating deficits and, 4) perinatal choline improves auditory gating in a gating deficient mouse strain. In Project 4 we will take advantage of the similarities between human and mouse with respect to alpha7 receptors and auditory gating to address fundamental biological questions regarding the specific role of alpha7 receptors and Chrna7 in normal and deficient auditory gating. The specific questions that will be addressed in Project 4 are 1) what is the molecular mechanism(s) through which genetic variability in Chrna7 leads to reduced expression of alpha7 recptors and auditory gating deficits 2) what is the neurobiological mechanism by which reduced expression of alpha7 receptors might lead to gating deficits? and 3) what is the mechanism through which perinatal choline improves auditory gating? Project 4 supports the clinical research of Projects 1 and 2. It performs molecular genetics experiments in parallel with Project 3, and it supports the phenotyping of mice in Projects 5 and 6.

该孔戴中心应用的研究者主要生成的数据提供了令人信服的证据，表明α7烟碱乙酰胆碱受体亚基是精神分裂症治疗干预的潜在靶标。这些数据包括观察结果，即精神分裂症患者海马中α7亚基的表达降低（Project 1），ChRNA7中的遗传变异，编码Alpha7亚基的基因与精神分裂症和听觉感觉缺陷（Project 3）和项目传感缺陷有关听觉门控缺陷在精神分裂症患者中很常见，选择性alpha7激动剂DMXB-A可以改善门控缺陷（项目1）。此外，α7选择性激动剂胆碱已被证明可以改善围产期给药时人类婴儿的听觉门控（项目2）。在小鼠中获得了惊人的类似数据。例如，我们在小鼠中表明1）听觉门控缺陷与降低的α7受体表达相关，2）CHRNA7中的遗传变异性与降低有关 Alpha7受体和听觉控球缺陷的表达，3）Alpha7受体选择性激动剂DMXB-A可改善门控缺陷，4）围产期胆碱可改善门控缺乏小鼠菌株中的听觉门控。在项目4中，我们将利用人与小鼠在α7受体和听觉门控之间的相似性，以解决有关alpha7受体和CHRNA7在正常和不足的听觉门口中的特定作用的基本生物学问题。项目4中将解决的具体问题是1）CHRNA7中遗传变异性的分子机制是什么导致α7接收器的表达降低和听觉门控缺陷2）什么是神经生物学机制，通过这些机制降低了α7受体的表达可能导致门控缺损？ 3）围产期胆碱改善听觉门控的机制是什么？项目4支持项目1和2的临床研究。它与项目3并行进行分子遗传学实验，并支持项目5和6中小鼠的表型。