Functional Analysis of 22q11 Schiz. Susceptibility Genes

22q11 Schiz 的功能分析。

基本信息

批准号：
6917081
负责人：
MARIA KARAYIORGOU
金额：
$ 28.67万
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 2007-05-31
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基因损伤，它会使个体患精神分裂症的风险比一般人群高出惊人的 25-31 倍，这一水平与生育两岁的个体的风险相当。患有精神分裂症的父母。这些微缺失在成年精神分裂症患者和严重儿童期发病的精神分裂症病例中的存在率明显高于一般人群。根据我们对 22q11 位点的所有单个基因进行广泛、详细的关联分析的结果，我们在此建议使用基因打靶和染色体工程方法来生成 3 个小鼠模型，这将帮助我们了解与精神分裂症风险增加相关的生物学基础。与这个地区。具体来说，我们建议破坏一个 250 Kb 的子区域，我们认为该子区域携带了大部分（如果不是全部）导致与该位点相关的精神分裂症风险显着增加的遗传元件。我们还建议从该位点产生两个单独基因的一般或有条件删除，根据我们对患者的遗传学研究，这可能是该区域疾病风险的很大一部分。我们建议检查我们将产生的行为表型小鼠品系，这些小鼠品系可以作为精神分裂症相关内表型（介导易感基因和临床诊断之间的病理生理过程的组成部分）的模型。此外，由于灰质损失是精神分裂症患者大脑中最一致的特征，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通用或空间限制的神经元或神经毡损失的可能性。最后，我们将使用寡核苷酸微阵列来解决大脑中因单个基因或基因簇的破坏而影响的分子和生理靶标的性质。对携带与人类精神分裂症相关的明确遗传缺陷的小鼠大脑中的表达模式进行分析，将为与该疾病相关的基因表达提供更准确和可重复的分析。这种综合方法与我们正在进行的患者遗传和神经认知研究相结合，将为了解与该区域相关的精神分裂症风险增加的生物过程提供重要的见解。此外，工程小鼠品系还将有助于鉴定具有抗精神病特性的新型且更具体的化合物。此类化合物的设计可以通过对缺失区域中导致精神分裂症易感性的单个基因的了解来指导。这将是精神分裂症遗传学和药物治疗领域前所未有的情况。