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GABAergic Dysfunction in Autism

自闭症中的 GABA 能障碍

基本信息

批准号：
7879275
负责人：
seyyed HOSSEIN FATEMI
金额：
$ 29.01万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-15 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7879275
关键词：
Adult Affect Age Apoptosis Area Atrophic Attention Autistic Disorder Autopsy Biochemical Brain Brain Pathology Brain region Cell Density Cells Cerebellar cortex structure Cerebellum Child Cognition Data Development Disease Down-Regulation Emotional Etiology Exhibits Functional disorder GABA Receptor Gene Family Gene Proteins Genes Genetic Gliosis Glutamate Decarboxylase Glutamates Growth Hippocampus (Brain)In Situ Hybridization Integrins Interneurons Laboratories Language Link Lobule Measures Memory Messenger RNA Modality Motor Nerve Tissue Neurodevelopmental Disorder Neurons Neuropil Neurotransmitters Outcome Parietal Parietal Lobe Pathology Peripheral Prevalence Proteins Proto-Oncogene Proteins c-akt Purkinje Cells Quantitative Reverse Transcriptase PCR Regulation Reporting Research Personnel Sampling Seizures Signal Transduction System Techniques Testing Visuospatial Western Blotting Work apolipoprotein E receptor 2 autistic children cell growth cholinergic early childhood expectation frontal lobe gamma-Aminobutyric Acid interest migration myelination neocortical neurotransmission programs receptor reelin protein sex transmission process young adult

项目摘要

DESCRIPTION (provided by applicant): Autism is a severe neurodevelopmental disorder with genetic and environmental etiologies and a prevalence rate of 16 per 10,000, which appears to result from altered development of nervous tissue pre- and postnatally. The central hypothesis of this application is that certain gene families involved in cell growth and migration and GABAergic neurotransmission will be altered in autism. This central hypothesis will be tested and the objectives of this application accomplished by pursuing two Specific Aims: 1) Determine the mRNA and protein levels for Reelin, its receptors, and downstream molecules in the Reelin signaling system in cerebellar, hippocampal, and frontal cortices of autistic subjects and matched controls; and 2) Determine the mRNA and protein levels for GAD 65 and 67 kDa proteins and GABA receptors in cerebellar, hippocampal, and frontal cortices of autistic subjects and matched controls. We will employ previously established qRTPCR, SDS-PAGE and western blotting, and in situ hybridization techniques to quantify various mRNA and protein species. It is our expectation that we will demonstrate gene and protein alterations in brains of autistics involving GABAergic markers, Reelin and its downstream components, linking GABAergic dysfunction to autistic brain structural abnormalities. Such outcomes will be significant, because they are expected to identify biochemical mechanisms responsible for abnormal brain development in early childhood, as seen in autism.

描述（由申请人提供）：自闭症是一种严重的神经发育障碍，具有遗传和环境病因，患病率为16/10，000，这似乎是由于出生前和出生后神经组织发育改变所致。本申请的中心假设是，自闭症患者中涉及细胞生长和迁移以及GABA能神经传递的某些基因家族将发生改变。将测试该中心假设，并且通过追求两个特定目的来实现本申请的目的：1）确定mRNA水平，和蛋白水平; 2）测定孤独症受试者和匹配对照的小脑、海马和额叶皮质中GAD 65和67 kDa蛋白和GABA受体的mRNA和蛋白水平。我们将采用先前建立的qRTPCR、SDS-PAGE和蛋白质印迹以及原位杂交技术来定量各种mRNA和蛋白质种类。我们期望我们将证明自闭症患者大脑中的基因和蛋白质改变，涉及GABA能标记物，Reelin及其下游成分，将GABA能功能障碍与自闭症大脑结构异常联系起来。这些结果将是重要的，因为它们有望确定导致儿童早期大脑发育异常的生化机制，如自闭症。