Mouse models for GABA epigenetic dysfunction

GABA 表观遗传功能障碍小鼠模型

基本信息

批准号：
7630485
负责人：
ALESSANDRO GUIDOTTI
金额：
$ 29.39万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-03-07 至 2010-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7630485
关键词：
Acetylation Adult Affinity Animal Model Antiepileptic Agents Antipsychotic Agents Appearance Applications Grants Area Attention Attenuated Behavior Behavioral Benzamides Binding Bipolar Disorder Brain Candidate Disease Gene Cell Nucleus Cerebral cortex CpG Islands Cytosine DNA DNA Modification Methylases Data Deacetylation Dendrites Dendritic Spines Disease Dose Down-Regulation Enzymes Epigenetic Process Equilibrium Euchromatin Event Exhibits Extracellular Domain Extracellular Matrix Functional disorder Future Gene Dosage Gene Expression Genes Genetic Polymorphism Heterochromatin Higher Order Chromatin Structure Hippocampus (Brain)Histone Deacetylase Inhibitor Histones Hypermethylation In Situ Hybridization Incidence Individual Integrins Interneurons Intervention Laboratories Lead Malignant Neoplasms Measurement Memory Messenger RNA Methionine Methylation Methyltransferase Modeling Modification Molecular Monozygotic twins Moods Morbidity - disease rate Mus Mutation N-terminal Neurons Neuropil Nucleosomes Outcome Study Patients Personal Communication Pharmaceutical Preparations Pharmacology Plastics Play Positioning Attribute Predisposing Factor Predisposition Prefrontal Cortex Principal Investigator Process Promoter Regions Protein Biosynthesis Proteins Psychiatrist Psychotic Disorders Recombinants Reeler Mouse Regulation Reporting Research Research Personnel Role Schizophrenia Signal Transduction Site Slice Sulpiride Symptoms Synapses Synaptic plasticity Syndrome Tail Technology Testing Therapeutic Transcriptional Regulation Treatment Efficacy Vorinostat Wild Type Mouse apicidin atypical antipsychotic base chromatin remodeling density design dizocilpine drug efficacy echistatin gamma-Aminobutyric Acid high risk hippocampal pyramidal neuron histone acetyltransferase inhibitor/antagonist mRNA Expression mouse model neoplastic cell neurochemistry neuropathology postsynaptic prevent programs promoter protein complex receptor research study transmission process valproate

项目摘要

DESCRIPTION (provided by applicant): The finding that schizophrenia (SZ) is a disorder characterized by a decrease of reelin and GAD67 (Guidotti et al., 2000), an increase of DNMT1 mRNA expression in cortical GABAergic interneurons (Costa et al., 2002a), and a hypermethylation of the reelin promoter CpG islands (Grayson, personal communication) encouraged us to consider that hypermethylation of promoter CpG islands is a mechanism operative in the dysfunction of GABAergic neurons in SZ. This project's overarching objective is to develop animal models of epigenetic reelin and GAD67 expression downregulation. We hypothesize that the downregulation of reelin and GAD67 in cortical GABAergic neurons of SZ brains can be replicated in mouse telencephalic GABAergic neurons with protracted administration of L-methionine in doses that increase: i) the content of the methyl donor S-adenosyl-methionine; ii) DNA-(cytosine-5)-methyltransferase (DNMT1) activity; and iii) covalent cytosine residues methylated in position 5 on the CpG-rich promoter regions of reelin and GADe? genes. One of the regulatory mechanisms involved in the process of control of gene activity by DNMT1 is its accessibility to target DNA segments. This accessibility may be regulated by the acetylated or deacetylated status of the nucleosomal core histones, which is governed by the balance of the activities of histone acetyltransferases (HAT) and histone deacetylases (HDAC). Studies in the field of cancer suggest that the increased activity of DNMTs observed in tumor cells can be downregulated by reducing HDAC activities with specific inhibitors. Hence, we have focused our attention on the action of HDAC inhibitors (i.e., valproate and benzamides) as putative drugs that may, by increasing core histone tail acetylation at nucleosomal sites, normalize in nuclei of telencephalic GABAergic neurons-reelin and GAD67 expression downregulation induced by hypermethylation of reelin or GAD67 promoter CpG islands. Recent reports suggest that typical and atypical antipsychotics are more potent, more efficacious, and less toxic if they are co-administered with valproate (VPA). The beneficial effects in the treatment of SZ obtained with the weak HDAC inhibitor VPA suggest that more potent HDAC inhibitors may represent a new opportunity for pharmacological interventions of putative therapeutic value in mitigating vulnerability to SZ among high risk individuals.

描述（由申请人提供）：发现精神分裂症（SZ）是一种疾病，其特征是reelin和gad67的降低（Guidotti等，2000），是皮质Gabaergic Interneurons中DNMT1 mRNA表达的增加（Costa等人（Costa等）（Costa等） 2002a），以及Reelin启动子CPG岛（Grayson，个人交流）的高甲基化鼓励我们认为启动子CpG岛的高甲基化是SZ GABA能神经元功能障碍的一种机制。该项目的总体目标是开发表观遗传reelin和GAD67表达下调的动物模型。我们假设，在小鼠脑脑脑脑型GABA能神经元中可以复制reelin和gad67在SZ大脑的皮质GABA能神经元中的下调，并以延长的l-甲二氨酸施用L-甲基氨酸的剂量，这些剂量增加了：I）增加：I） ii）DNA-（Cytosine-5） - 甲基转移酶（DNMT1）活性； iii）在Reelin和Gade的富含CpG启动子区域的位置5中甲基化的共价胞嘧啶残基？基因。 DNMT1控制基因活性过程中涉及的调节机制之一是其对目标DNA段的可及性。这种可及性可以受核小体核心组蛋白的乙酰化或脱乙酰化状态调节，核小体核心组蛋白受组蛋白乙酰基转移酶（HAT）和组蛋白脱乙酰基酶（HDAC）的平衡控制。在癌症领域的研究表明，在肿瘤细胞中观察到的DNMT活性的增加可以通过减少具有特定抑制剂的HDAC活性来下调。因此，我们将注意力集中在HDAC抑制剂（即丙戊酸和苯甲胺）的作用上，作为推定的药物，可以通过增加核小体部位的核心组蛋白尾乙酰化，在核小体部位增加脑脑化的脑脑化指示的GABAGAERONGICIN-RENURONS-RERORONS-RERELIN和GAD67表现量表，并归一化。通过reelin或GAD67启动子CPG岛的高甲基化。最近的报道表明，如果与丙戊酸（VPA）共同管理，典型和非典型的抗精神病药更有效，更有效且毒性较小。用弱HDAC抑制剂VPA获得的SZ的有益作用表明，更有效的HDAC抑制剂可能代表了推定治疗价值的新机会，以减轻高风险个体中SZ的脆弱性。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The Decrease of n-3 Fatty Acid Energy Percentage in an Equicaloric Diet Fed to B6C3Fe Mice for Three Generations Elicits Obesity.

DOI：
10.1155/2009/867041
发表时间：
2009
期刊：
Cardiovascular psychiatry and neurology
影响因子：
0
作者：
Hanbauer I;Rivero-Covelo I;Maloku E;Baca A;Hu Q;Hibbeln JR;Davis JM
通讯作者：
Davis JM

Epigenetic GABAergic targets in schizophrenia and bipolar disorder.

DOI：
10.1016/j.neuropharm.2010.10.021
发表时间：
2011-06
期刊：
NEUROPHARMACOLOGY
影响因子：
4.7
作者：
Guidotti, A.;Auta, J.;Chen, Y.;Davis, J. M.;Dong, E.;Gavin, D. P.;Grayson, D. R.;Matrisciano, F.;Pinna, G.;Satta, R.;Sharma, R. P.;Tremolizzo, L.;Tueting, P.
通讯作者：
Tueting, P.

L-methionine decreases dendritic spine density in mouse frontal cortex.