Functional Analysis of 22q11 Schiz. Susceptibility Genes

22q11 Schiz 的功能分析。

基本信息

批准号：
7092528
负责人：
MARIA KARAYIORGOU
金额：
$ 3.86万
依托单位：
ROCKEFELLER UNIVERSITY
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 2006-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Microdeletions of the 22q11 locus are the only known genetic lesions that increase an individual's risk for schizophrenia to a striking 25-31 times over the general population risk, a level comparable to the risk of an individual born to two schizophrenic parents. These microdeletions are present among adult schizophrenics and cases of severe childhood onset schizophrenia at rates significantly higher than in the general population. Based on our results from an extensive, detailed association analysis of all individual genes from the 22q11 locus, we propose here to use gene targeting and chromosomal engineering approaches to generate 3 mouse models that will help us understand the biological basis of the increased schizophrenia risk associated with this region. Specifically, we propose to disrupt a 250 Kb subregion that we believe carries most, if not all the genetic elements responsible for the striking increase for schizophrenia risk associated with this locus. We also propose to generate general or conditional deletions of two individual genes from this locus which, according to our genetic studies in patients, may account for a large part of the disease risk attributed to this region. We propose to examine the strains of mice that we will generate for behavioral phenotypes that may serve as models of schizophrenia-related endophenotypes (components of pathophysiological processes mediating between predisposing genes and clinical diagnosis). Furthermore, and because gray matter loss is the most consistent feature in brains of schizophrenic patients, we will address the possibility of generic or spatially restricted neuron or neuropil loss in the brains of the mutant mice using a battery of sophisticated histochemical and imaging approaches. Finally, we will use oligonucleotide microarrays to address the nature of the molecular and physiological targets affected in the brain by the disruption of individual genes or clusters of genes. Analysis of expression patterns in the brains of mice that carry well-defined genetic deficits associated with schizophrenia in humans will provide a more accurate and reproducible profiling of gene expression associated with the disease. This comprehensive approach, in conjunction with our ongoing genetic and neurocognitive studies in patients, will provide important insights into the biological processes underlying the increased schizophrenia risk associated with this region. Furthermore, the engineered mouse strains will also facilitate the identification of novel and more specific compounds with neuroleptic properties. The design of such compounds can be directed by the knowledge of individual genes from the deleted region that contribute to schizophrenia susceptibility. This will be an unprecedented situation in schizophrenia genetics and pharmacotherapy.

描述（由申请人提供）：22q11基因座的微缺失是唯一已知的遗传病变，它增加了一个人的精神分裂症风险比普通人群风险高25-31倍，这是一个与两个精神分裂症父母出生的个人的风险相当的水平。这些微缺失存在于成年精神分裂症患者中，而精神分裂症的严重童年开始，其速率显着高于普通人群。基于我们对22q11基因座的所有单个基因的广泛，详细的关联分析的结果，我们在这里建议使用基因靶向和染色体工程方法生成3种小鼠模型，以帮助我们了解与该地区相关的精神分裂症风险增加的生物学基础。具体而言，我们建议破坏一个250 kb的子区域，我们认为，我们认为最多的，即使不是所有的遗传因素，这些遗传因素导致与该基因座相关的精神分裂症风险的惊人增加。我们还建议从该基因座中产生两个单独基因的一般或条件缺失，根据我们在患者中的遗传研究，这可能是由于该地区造成的很大一部分疾病风险。我们建议检查可能作为与精神分裂症相关的内向型型模型的行为表型生成的小鼠菌株（在倾向基因和临床诊断之间介导的病理生理过程的成分）。此外，由于精神分裂症患者的大脑中灰质损失是最一致的特征，因此我们将使用一系列复杂的组织化学和成像方法来解决突变小鼠大脑中仿制或空间限制神经元或神经纤维损失的可能性。最后，我们将使用寡核苷酸微阵列来解决通过基因或基因簇的破坏在大脑中影响的分子和生理靶标的性质。分析与人类精神分裂症相关的遗传缺陷的小鼠大脑中的表达模式将提供与该疾病相关的基因表达的更准确和可重复的分析。这种全面的方法与我们在患者中正在进行的遗传和神经认知研究结合在一起，将为与该地区相关的精神分裂症风险增加的生物学过程提供重要的见解。此外，工程的小鼠菌株还将促进具有神经摄影特性的新型和更特定的化合物的鉴定。此类化合物的设计可以通过从已删除区域的各个基因的知识来指导，这有助于精神分裂症易感性。这将是精神分裂症遗传学和药物治疗的前所未有的情况。