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

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

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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，有22q11.2微骨骼的儿童中约有30％会在青春期或成年早期患上精神分裂症或精神分裂症。认知缺陷和精神病症状的遗传基础受到严格审查。我们自己从该基因座鉴定精神分裂症敏感性基因的努力是基于这样的假设：22q11基因中的变异可能会调节一般（核型正常）人群中的疾病风险，并使用了大型家庭样本，随后进行了研究适当设计的小鼠模型的研究。特别是我们对PODH基因的研究，以及其他实验室的独立确认工作，提供了令人信服的证据，表明PODH水平的缺乏（以及L-殖民水平的随之而来的增加）是精神病性和可能与22q11微型实质相关的认知症状的重要原因。在这里，我们建议深入分析两种其他生物学过程的影响，我们发现，由于22q11微缺失，我们发现它们受到影响，这可能会影响几种大脑表达基因的神经元发育，突触可塑性和蛋白质丰度。具体而言，我们建议利用最近在我们的实验室中产生的三种可靠的鼠标模型，以及一系列复杂的形态，电生理和行为方法，以促进对这两个重要的物理学在体内的更好理解，并影响22q11微液位对这两个重要的生理过程如何影响，尤其影响了两种大脑区域的功能，并涉及大脑区域的功能，该区域构成了范围内的区域。与这种疾病相关的内型型。我们提出的分析有望提供有价值的见解，以了解22q11基因座增加精神分裂症的风险和相关的认知末端表型。我们提出的研究还将提供良好的动物模型，可用于检验进一步的假设并促进未来的药物开发工作。确实，该提案的主要动机是利用现有的遗传知识来确定可以改善当前可用治疗方法的新药物。