Glutamate Transporter Expression in Schizophrenia

精神分裂症中谷氨酸转运蛋白的表达

• 批准号: 7488014
• 负责人: Robert E McCullumsmith
• 金额: $ 17.44万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-28 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7488014
• 关键词: Address; Affect; Amino Acid Transporter; Animals; Antipsychotic Agents; Arts; Autopsy; Award; Binding; Bioinformatics; Biometry; Brain; Brain region; Carrier Proteins; Cell membrane; Cells; Chromosome Pairing; Chronic; Co-Immunoprecipitations; Control Groups; Data; Decision Making; Electrophysiology (science); Excitatory Amino Acids; Exposure to; Family; Functional Magnetic Resonance Imaging; Functional disorder; Gene Deletion; Gene Expression; Gene Expression Regulation; Gene Targeting; Gene Transfer; Genes; Genetic; Glutamate Receptor; Glutamate Transporter; Glutamates; Goals; Haloperidol; Human; Image; Kinetics; Laboratories; Lasers; Learning; Limbic System; Link; Localized; Long-Term Potentiation; Measurement; Measures; Medial Dorsal Nucleus; Mediating; Membrane Proteins; Mental Health; Mentors; Methodology; N-Methyl-D-Aspartate Receptors; Neuroglia; Neurons; Patients; Phosphorylation; Polymerase Chain Reaction; Population; Positron-Emission Tomography; Post-Translational Protein Processing; Prefrontal Cortex; Protein Overexpression; Proteins; Psychopathology; Quantitative Microscopy; Rate; Rattus; Recombinants; Regulation; Research; Research Methodology; Research Personnel; Research Project Grants; Research Training; Rodent; Schizophrenia; Series; Short-Term Memory; Signal Transduction; Simulate; Slice; Synapses; Synaptic Cleft; Synaptic plasticity; System; Techniques; Thalamic structure; Theoretical Studies; Time; Tissues; Training; Transcript; Viral; Viral Vector; career; clinical epidemiology; cognitive function; cohort; design; experience; glycosylation; hippocampal pyramidal neuron; human study; in vivo; innovation; interest; mRNA Expression; neurochemistry; neurotransmission; programs; recombinase; research study; reuptake; skills; tool; transmission process

DESCRIPTION (provided by applicant): The overall goal of this Mentored Research Career Award (K08) application is to provide training in innovative techniques that will permit the applicant to ask and answer the largest possible questions in translational mental health research. This research training plan has two overall objectives. The first is to train the applicant in new cutting-edge techniques to study gene expression in postmortem tissue. The second is for the applicant to learn how to perform and evaluate inducible gene deletion or overexpression in the rodent brain. To achieve these objectives, the applicant has planned a series of complementary educational and research training experiences, including formal coursework in biostatistics, bioinformatics, clinical epidemiology, genetics and signal transduction, as well as extended laboratory experiences with consultants to learn electrophysiology, laser capture microscopy (LCM), quantitative PCR, and gene manipulation techniques with viral vectors. In concert with this application's overall objectives, we have designed a research project that maximizes the applicant's exposure to innovative research methodologies and builds on his previous findings of glutamate transporter transcript abnormalities in schizophrenia. These data suggest abnormalities of glutamate transporter expression in corticothalamic circuits in schizophrenia. Accordingly, we hypothesize that expression and regulation of excitatory amino acid transporters (EAATs) is altered in corticothalamic circuits in schizophrenia, contributing to psychopathology in this illness. To evaluate this hypothesis we will measure EAAT mRNA expression in populations of microdissected cells and examine post-translational modification of EAAT proteins in subjects with schizophrenia and a control group. Guided by these human studies, we will then characterize the electrophysiological and neurochemical consequences associated with corticothalamic alterations of transporter gene expression generated using viral mediated gene transfer and/or the cre-loxP recombinase system. These studies will link identified changes in gene expression in schizophrenia with circuit specific alterations in glutamate synapse composition and function. At the conclusion of this set of experiments, the applicant will have learned innovative, state-of-the-art techniques for investigating abnormalities of gene expression and regulation in severe psychiatric illness, providing the tools needed to develop an independent research program.

描述（由申请人提供）：本指导研究职业奖（K08）申请的总体目标是提供创新技术培训，使申请人能够提出并回答转化心理健康研究中尽可能多的问题。该研究培训计划有两个总体目标。首先是对申请人进行新的尖端技术培训，以研究死后组织中的基因表达。第二个是让申请人学习如何执行和评估啮齿类动物大脑中的诱导基因缺失或过度表达。为了实现这些目标，申请人计划了一系列补充性的教育和研究培训经验，包括生物统计学、生物信息学、临床流行病学、遗传学和信号转导方面的正式课程，以及与顾问一起学习电生理学、激光捕获显微镜（LCM）、定量PCR和病毒载体基因操作技术的扩展实验室经验。与本申请的总体目标相一致，我们设计了一个研究项目，最大限度地提高申请人接触创新研究方法的机会，并以他之前关于精神分裂症谷氨酸转运蛋白转录异常的发现为基础。这些数据表明精神分裂症皮质丘脑回路中谷氨酸转运蛋白表达异常。因此，我们假设精神分裂症皮质丘脑回路中兴奋性氨基酸转运蛋白（EAAT）的表达和调节发生改变，从而导致这种疾病的精神病理学。为了评估这一假设，我们将测量显微切割细胞群中 EAAT mRNA 的表达，并检查精神分裂症受试者和对照组中 EAAT 蛋白的翻译后修饰。在这些人体研究的指导下，我们将描述与使用病毒介导的基因转移和/或 cre-loxP 重组酶系统产生的转运蛋白基因表达的皮质丘脑改变相关的电生理学和神经化学后果。这些研究将把精神分裂症基因表达的变化与谷氨酸突触组成和功能的电路特异性改变联系起来。在这组实验结束时，申请人将学到用于研究严重精神疾病中基因表达和调控异常的创新、最先进的技术，从而提供开发独立研究项目所需的工具。