Functional Analysis of 22q11 Schiz. Susceptibility Genes

描述（由申请人提供）：22 q11基因座的微缺失是唯一已知的遗传病变，它使个体患精神分裂症的风险增加到一般人群风险的25-31倍，这一水平与父母患有精神分裂症的个体的风险相当。这些微缺失存在于成年精神分裂症患者和严重的儿童期发作的精神分裂症病例中，其发生率显著高于一般人群。 基于我们对22 q11位点所有个体基因进行广泛、详细的关联分析的结果，我们建议使用基因靶向和染色体工程方法来生成3种小鼠模型，这将有助于我们了解与该区域相关的精神分裂症风险增加的生物学基础。具体来说，我们建议破坏一个250 Kb的亚区域，我们认为该亚区域携带了大多数（如果不是所有）与该基因座相关的精神分裂症风险显著增加的遗传因素。我们还建议从该位点产生两个单独基因的一般或条件性缺失，根据我们对患者的遗传研究，这可能是归因于该区域的疾病风险的很大一部分。 我们建议检查小鼠品系，我们将产生的行为表型，可能作为精神分裂症相关的内表型（易感基因和临床诊断之间介导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，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性神经元或神经元丢失的可能性。最后，我们将使用寡核苷酸微阵列来解决在大脑中受单个基因或基因簇破坏影响的分子和生理靶点的性质。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，结合我们正在进行的遗传和神经认知研究的患者，将提供重要的见解的生物过程的基础上增加精神分裂症的风险与该地区。此外，工程小鼠品系还将有助于鉴定具有神经安定特性的新型和更特异性的化合物。这些化合物的设计可以由来自缺失区域的有助于精神分裂症易感性的单个基因的知识指导。这将是精神分裂症遗传学和药物治疗中前所未有的情况。

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.