Functional Analysis of 22q11 Schiz. Susceptibility Genes

描述(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。22q11.2微缺失的个体表现出一系列的认知缺陷。值得注意的是，在22q11.2微缺失的儿童中，约30%的儿童在青春期或成年早期会患上精神分裂症或分裂情感障碍。认知缺陷和精神症状的遗传基础正在接受严格的审查。我们自己从这个基因座识别精神分裂症易感基因的努力是基于这样的假设，即22q11基因的变异可能调节普通(核型正常)人群的疾病风险，并使用了大量的家庭样本，并对适当设计的小鼠模型进行了后续研究。特别是我们对PROSH基因的研究，以及其他实验室的独立验证工作，已经提供了令人信服的证据，即PROSH水平的缺乏(以及随之而来的L-Pro水平的增加)是与22q11微缺失相关的精神症状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由于22q11微缺失而受到影响的另外两个生物学过程的影响，这两个过程可能会影响神经元发育、突触可塑性和几个脑表达基因的蛋白质丰度。具体地说，我们建议利用我们实验室最近建立的三个可靠的小鼠模型和一系列复杂的形态、电生理和行为方法，以便在体内更好地了解22q11微缺失损害的这两个重要生理过程如何影响海马区和前额叶皮质的功能，这两个脑区与精神分裂症的发病机制有关，特别是与精神分裂症相关的认知内表型。我们提出的分析有望为22q11基因座如何增加精神分裂症和相关认知内表型受损的风险提供有价值的见解。我们提议的研究还将提供具有良好特征的动物模型，可以用来检验进一步的假设并促进未来的药物开发努力。事实上，这项提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，以改进现有的治疗方法。

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.