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Translating OCD gene-association studies into mice to examine SLC1A1 function

将强迫症基因关联研究转化为小鼠以检查 SLC1A1 功能

基本信息

批准号：
8727759
负责人：
Susanne Elizabeth Ahmari
金额：
$ 15.06万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-30 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8727759
关键词：
Alleles Anxiety Autopsy Behavior Behavioral Biochemical Biological Assay Biological Models Brain Brain region Candidate Disease Gene Cell model Chronic Clinical Code Corpus striatum structure Development Disease Dissection Event Functional disorder Gene Expression Gene Targeting Generations Genes Genetic Glutamate Transporter Glutamates Glutathione Grant Grooming High Pressure Liquid Chromatography Human Human Genetics Immunohistochemistry In Situ Institutes Investigation Knock-in Mouse Lead Link Measurement Measures Mediating Mental disorders Modeling Molecular Molecular Abnormality Mus Neurons Neurotransmitters New York Obsessive-Compulsive Disorder Patients Prevalence Proteins Regulation Research Research Personnel Reversal Learning Risk Factors Role Scientist Side Signal Transduction Simulate Specificity Staining method Stains Structure Symptoms Synapses Synaptosomes System Technology Testing Thalamic structure Time Tissues Transgenic Mice Translating Universities Western Blotting Work base behavior test brain tissue clinical phenotype critical developmental period early onset excitatory amino acid transporter 3 flexibility gamma-Aminobutyric Acid in vivo interest mouse model neurochemistry novel overexpression postsynaptic prepulse inhibition protein transport research study severe mental illness transmission process

项目摘要

DESCRIPTION (provided by applicant): Support is requested for a 2-year collaborative grant between scientists at the New York State Psychiatric Institute and Vanderbilt University to investigate the pathophysiology underlying OCD. The proposal bridges basic and clinical OCD research by integrating findings from the research team's ongoing human studies into the proposed mouse experiments. The research plan thus capitalizes on the expertise of the team in 1) human OCD genetic studies, 2) development of transgenic mice, 3) biochemical assays, and 4) mouse behavioral analysis. Current understanding of the molecular and cellular abnormalities underlying OCD is limited, in part because post-mortem studies in humans have not been performed. In addition, mouse studies have not yet been convincingly linked to the clinical phenotype and genetic abnormalities seen in OCD patients. To date, the only gene which has been consistently linked to OCD in human genetic studies is SLC1A1, which codes for a protein that transports the neurotransmitter glutamate. In addition, there is evidence from human studies that abnormal regulation of glutamate transmission in striatum is correlated with OCD symptoms. This has led to the hypothesis that abnormal levels of the SLC1A1 glutamate transporter in striatum lead to 1) abnormalities in the glutamate system, 2) changes in brain structure, and 3) OCD symptoms. The proposed R21 will test this hypothesis using novel transgenic mouse technology. In the first aim, the researchers will use an efficient system they have previously developed for manipulating gene expression in mice called the FAST system (Flexible Accelerated STOP TetO-knockin). This will allow them to develop a novel transgenic mouse line called tetO-Slc1a1, which will permit precise regulation of SLC1A1 expression levels in brain regions implicated in OCD. They will then use this mouse line to generate abnormally high levels of the SLC1A1 glutamate transporter specifically in striatum. This will simulate the effect of the version of the gene found most commonly in OCD patients. In the second aim, the mice with abnormally high levels of the OCD-associated gene will be characterized by: 1) measuring glutamate system functioning~ 2) examining brain structure~ and 3) testing behavior in OCD-relevant paradigms that measure anxiety and repetitive behaviors. This will provide the first direct test of whether OCD-related dysfunction is caused by abnormal expression of the leading human OCD candidate gene. Completion of this grant will lead to an amenable system for 1) further dissection of the molecular, cellular, and electrophysiologic underpinnings of observed changes~ and 2) determination of whether there is a particular time in development during which the brain is more vulnerable to developing OCD. These studies will lead to a better understanding of how dysfunctional circuits lead to OCD symptoms, which is necessary to guide development of new treatments for this severe mental illness.

描述（由申请人提供）：要求支持纽约州立精神病研究所和范德比尔特大学的科学家之间为期2年的合作赠款，以调查强迫症的病理生理学基础。该提案通过将研究小组正在进行的人类研究的结果整合到拟议的小鼠实验中，将基础和临床强迫症研究联系起来。因此，该研究计划利用了该团队在以下方面的专业知识：1）人类强迫症遗传研究，2）转基因小鼠的开发，3）生化测定，4）小鼠行为分析。目前对强迫症潜在的分子和细胞异常的理解是有限的，部分原因是还没有进行人类的死后研究。此外，小鼠研究尚未令人信服地与强迫症患者的临床表型和遗传异常联系起来。迄今为止，在人类遗传学研究中，唯一与强迫症相关的基因是SLC 1A 1，它编码一种转运神经递质谷氨酸的蛋白质。此外，有来自人类研究的证据表明，纹状体中谷氨酸传输的异常调节与强迫症症状相关。这导致了以下假设：纹状体中SLC 1A 1谷氨酸转运蛋白水平异常导致1）谷氨酸系统异常，2）脑结构变化，3）强迫症症状。拟议中的R21将使用新的转基因小鼠技术来验证这一假设。在第一个目标中，研究人员将使用他们以前开发的一种有效系统来操纵小鼠的基因表达，称为FAST系统（灵活加速停止TetO敲入）。这将使他们能够开发一种名为tetO-Slc 1a 1的新型转基因小鼠品系，这将允许精确调节与强迫症有关的大脑区域中的SLC 1A 1表达水平。然后，他们将使用这种小鼠品系在纹状体中特异性地产生异常高水平的SLC 1A 1谷氨酸转运蛋白。这将模拟在强迫症患者中最常见的基因版本的效果。在第二个目标中，具有异常高水平强迫症相关基因的小鼠的特征将包括：1）测量谷氨酸系统功能~ 2）检查大脑结构~和3）在强迫症相关范式中测试行为，以测量焦虑和重复行为。这将提供第一个直接测试，以确定OCD相关功能障碍是否由人类OCD候选基因的异常表达引起。完成这项资助将导致一个适合的系统，用于1）进一步解剖观察到的变化的分子，细胞和电生理基础，以及2）确定大脑在发育过程中是否有一个特定的时间更容易发生强迫症。这些研究将有助于更好地了解功能失调的电路如何导致强迫症症状，这对于指导这种严重精神疾病的新治疗方法的开发是必要的。