Functions of DISC1 and APP in Cortical Development and Neuropsychiatric Disorders

DISC1 和 APP 在皮质发育和神经精神疾病中的功能

基本信息

批准号：
7571144
负责人：
Tracy L YOUNG-PEARSE
金额：
$ 9万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
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：
2009-06-01 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7571144
关键词：
Academic Training Address Affect Alzheimer&apos s Disease Amyloid beta-Protein Precursor Area Autistic Disorder Binding Biochemistry Biological Assay Brain Cell Nucleus Centrosome Complement Coupling DISC1 protein Defect Development Disease Dopamine Dyslexia Electroporation Embryo Epilepsy ErbB4 gene Etiology Foundations Future Genes Genetic Genetic Variation Glutamates Goals High Pressure Liquid Chromatography Human Immigration Immunohistochemistry Integral Membrane Protein Knowledge Laboratories Lead Link Mediating Mental Retardation Mental disorders Mentors Methods Microdialysis Microscopy Molecular Mutant Strains Mice Mutate Mutation NRG1 gene Neurites Neuronal Migration Disorder Neurons Neurotransmitter Receptor Neurotransmitters Outcome PDE4B Pathway interactions Patients Pediatric Hospitals Phenotype Play Principal Investigator Process Proteins Psychiatry Psychotic Disorders RNA Splicing Rattus Reagent Research Risk Risk Factors Rodent Role Schizophrenia Signal Pathway Signal Transduction Symptoms System Technical Expertise Tracer Training Variant Western Blotting apolipoprotein E receptor 2 base cell motility experience extracellular gamma-Aminobutyric Acid genetic analysis genetic manipulation immunocytochemistry in utero in vivo inhibitor/antagonist insight lectures lissencephaly medical schools meetings migration neuron development neuropsychiatry neurotransmission olfactomedin positional cloning programs protein distribution receptor receptor expression research study small hairpin RNA

项目摘要

DESCRIPTION (provided by applicant): Defects of cortical cell migration have been linked to a spectrum of phenotypes that include epilepsy, mental retardation, autism, and schizophrenia (SZ). In the past, functional analyses of human genes linked to classic disorders of neuronal migration such as lissencephaly have yielded valuable insights into the pathways involved in migration and the underlying causes of these diseases. Studies in rodents have added additional factors to the list of genes necessary for migration. One such factor is Amyloid Precursor Protein (APP), an Alzheimer's Disease linked gene, which is required for both normal migration into the cortical plate and neuronal process outgrowth. In addition, several genes have been linked to schizophrenia such as DISC1, PDE4, and NRG1, all of which play important roles in neuronal development, including migration and neurite outgrowth. Recent studies link classic pathways of migration involving factors such as APOER2, DAB1, and LIS1 with both APP and certain SZ-linked genes. This application aims to 1) integrate these newly identified players into established migration and neurite outgrowth pathways; 2) elucidate how certain mutations and variants in SZ-associated genes lead to defects in migration; and 3) address whether defects in migration and/or subtle alterations in neuronal process outgrowth lead to altered levels of neurotransmitters and their receptors, both of which are described in patients with SZ. The in vivo method of in utero electroporation will be used to express shRNAs or cDNAs encoding wild type or mutated versions of candidate proteins to assess the effects of their altered expression on neuronal precursor migration in the context of the embryonic rat brain. Primary neuronal cultures also will be utilized to analyze the effects of these various constructs on neuronal process outgrowth. Lastly, both neurotransmitter receptor expression (using biochemistry and immunohistochemistry) and neurotransmitter levels (using microdialysis and HPLC) will be analyzed in rodents in which different genetic manipulations have caused varying degrees of disordered cortical migration. This set of experiments will address the hypothesis that abnormalities in neuronal migration are linked to defects in the neurotransmitter systems that are observed in patients with SZ.

描述（由申请人提供）：皮质细胞迁移的缺陷已与包括癫痫，智力低下，自闭症和精神分裂症（SZ）的表型相关。过去，与神经元迁移的经典疾病有关的人类基因的功能分析（如lisscephaly）对涉及迁移的途径和这些疾病的根本原因产生了宝贵的见解。啮齿动物的研究为迁移所需的基因列表添加了其他因素。这样的因素之一是淀粉样蛋白前体蛋白（APP），阿尔茨海默氏病连接的基因，这是正常迁移到皮质板和神经元过程的生长所必需的。此外，几个基因与精神分裂症（例如Disc1，PDE4和NRG1）有联系，所有这些基因在神经元发育中起着重要作用，包括迁移和神经突生长。最近的研究将涉及ApoER2，DAB1和LIS1等因素的经典迁移途径与APP和某些SZ相关基因联系起来。该应用程序旨在1）将这些新确定的参与者整合到已建立的迁移和神经突生长途径中； 2）阐明SZ相关基因中的某些突变和变异如何导致迁移缺陷； 3）解决迁移和/或神经元过程中的细微变化的缺陷是否导致神经递质及其受体的水平改变，这两者在SZ患者中均描述。子宫电穿孔中的体内方法将用于表达编码野生型或突变版本的候选蛋白的shRNA或cDNA，以评估其在胚胎大鼠脑的上下文中其改变其表达对神经元前体迁移的影响。原发性神经元培养物还将用于分析这些各种构建体对神经元过程生长的影响。最后，在不同遗传操作导致不同遗传操作的不同遗传操作的啮齿动物中，将分析神经递质受体表达（使用生物化学和免疫组织化学）和神经递质水平（使用微透析和HPLC）。这组实验将解决以下假设：神经元迁移的异常与在SZ患者中观察到的神经递质系统中的缺陷有关。