Functional Analysis of 22q11 Schiz. Susceptibility Genes

22q11 Schiz 的功能分析。

基本信息

批准号：
8196900
负责人：
MARIA KARAYIORGOU
金额：
$ 56.51万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-07-01 至 2013-08-07
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8196900
关键词：
22q11 22q11.2 Accounting Address Adolescence Affect Animal Model Animals Area Behavioral Biogenesis Biological Biological Models Biological Process Brain Brain region Child Chromosome abnormality Code Cognition Disorders Cognitive Cognitive deficits Dendritic Spines Development Disease Drug Delivery Systems Exhibits Family Follow-Up Studies Funding Future Genes Genetic Genetic Research Genome Goals Hippocampus (Brain)Human Human Genetics Image Impaired cognition In Vitro Individual Investigation Knock-out Knockout Mice Knowledge Light Mediating Mental disorders MicroRNAs Modeling Molecular Molecular Profiling Motivation Mus Mutant Strains Mice Neurobehavioral Manifestations Neurons Organism Pathogenesis Pathway interactions Performance Phenotype Physiological Processes Play Population Predisposition Prefrontal Cortex Process Proline Protein Family Proteins Research Risk Role Sampling Schizoaffective Disorders Schizophrenia Series Susceptibility Gene Symptoms Synapses Synaptic Transmission Synaptic plasticity Syndrome Testing Transcript Translational Research Variant Work base behavior test brain morphology design disability disorder risk drug development emerging adult endophenotype follow-up genetic analysis genetic association genetic linkage genetic risk factor improved in vivo insight member microdeletion mouse model neural circuit neuron development novel palmitoylation pre-clinical research study synaptogenesis therapy development

项目摘要

DESCRIPTION (provided by applicant): Hemizygous microdeletions of the 22q11.2 locus are among the most common chromosomal abnormalities. Individuals with the 22q11.2 microdeletion exhibit a spectrum of cognitive deficits. Notably, ~30% of children with the 22q11.2 microdeletion will develop schizophrenia or schizoaffective disorder in adolescence or early adulthood. The genetic basis of the cognitive deficits and psychiatric symptoms is under intense scrutiny. Our own efforts to identify schizophrenia-susceptibility genes from this locus were based on the assumption that variants in 22q11 genes may modulate disease risk in the general (karyotypically normal) population and used large family samples followed up by studies in appropriately designed mouse models. Our studies on the PRODH gene, in particular, along with independent confirmatory work by other labs have provided compelling evidence that deficiency in the levels of PRODH (and the ensuing increase in L-proline levels) is an important contributor to the psychotic and possibly cognitive symptoms associated with the 22q11 microdeletions. Here, we propose to analyze in depth the effects of two additional biological processes that we discovered to be affected as a result of the 22q11 microdeletions, which are likely to affect neuronal development, synaptic plasticity and protein abundance of several brain expressed genes. Specifically, we propose to utilize three reliable mouse models recently generated in our labs and a series of sophisticated morphological, electrophysiological and behavioral approaches to facilitate a better understanding in vivo of how these two important physiological processes impaired by the 22q11 microdeletions, affect the function of hippocampus and prefrontal cortex, two brain regions implicated in the pathogenesis of schizophrenia and especially the cognitive endophenotypes associated with this disorder. Our proposed analysis promises to provide valuable insights on the ways the 22q11 locus increases the risk of schizophrenia and related impaired cognitive endophenotypes. Our proposed research will also provide well-characterized animal models that can be used to test further hypotheses and facilitate future drug development efforts. Indeed, a major motivation for this proposal is to exploit existing genetic knowledge to identify new drug targets that will improve currently available treatments.

描述（由申请人提供）：22q11.2 基因座的半合子微缺失是最常见的染色体异常之一。具有 22q11.2 微缺失的个体表现出一系列认知缺陷。值得注意的是，约 30% 具有 22q11.2 微缺失的儿童将在青春期或成年早期患上精神分裂症或分裂情感障碍。认知缺陷和精神症状的遗传基础正在受到密切关注。我们自己从该位点鉴定精神分裂症易感基因的努力是基于这样的假设：22q11 基因的变异可能会调节一般（核型正常）人群的疾病风险，并使用大量家庭样本，随后在适当设计的小鼠模型中进行研究。特别是我们对 PRODH 基因的研究以及其他实验室的独立验证工作提供了令人信服的证据，表明 PRODH 水平的缺乏（以及随之而来的 L-脯氨酸水平的增加）是导致精神病和可能的认知障碍的重要因素。与 22q11 微缺失相关的症状。在这里，我们建议深入分析另外两个生物过程的影响，我们发现这两个生物过程因 22q11 微缺失而受到影响，这可能会影响神经元发育、突触可塑性和几个大脑表达基因的蛋白质丰度。具体来说，我们建议利用我们实验室最近生成的三个可靠的小鼠模型以及一系列复杂的形态学、电生理学和行为学方法，以帮助更好地了解体内 22q11 微缺失损害的这两个重要的生理过程如何影响小鼠的功能。海马体和前额叶皮层，这两个大脑区域与精神分裂症的发病机制有关，尤其是与这种疾病相关的认知内表型。我们提出的分析有望为 22q11 基因座增加精神分裂症和相关认知内表型受损的风险提供有价值的见解。我们提出的研究还将提供特征良好的动物模型，可用于测试进一步的假设并促进未来的药物开发工作。事实上，该提案的一个主要动机是利用现有的遗传知识来识别新的药物靶点，从而改善当前可用的治疗方法。