Functional Analysis of 22q11 Schiz. Susceptibility Genes

描述（由申请人提供）：22q11.2位点的半合子微缺失是最常见的染色体异常之一。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%患有22q11.2微缺失的儿童会在青春期或成年早期患上精神分裂症或分裂情感性障碍。认知缺陷和精神症状的遗传基础正在受到严格的审查。基于22q11基因的变异可能调节一般（核型正常）人群的疾病风险的假设，我们自己从这个位点鉴定精神分裂症易感基因的努力，使用了大量的家族样本，并在适当设计的小鼠模型中进行了研究。我们对PRODH基因的研究，特别是与其他实验室的独立验证工作一起，提供了令人注目的证据，证明PRODH水平的缺乏（以及随之而来的l -脯氨酸水平的增加）是与22q11微缺失相关的精神病和可能的认知症状的重要因素。在这里，我们建议深入分析我们发现的受22q11微缺失影响的另外两个生物过程的影响，这些过程可能影响神经元发育、突触可塑性和几个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种可靠的小鼠模型和一系列复杂的形态学、电生理和行为学方法，以便更好地了解22q11微缺失如何影响这两个重要的生理过程，从而影响海马和前额叶皮质的功能。涉及精神分裂症发病机制的两个大脑区域，特别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风险的方式提供有价值的见解。我们提出的研究还将提供具有良好特征的动物模型，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，提出这一建议的一个主要动机是利用现有的遗传知识来确定新的药物靶点，从而改善目前可用的治疗方法。

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.