Functional Genomics of Neuroplasticity in Schizophrenia

描述（由申请人提供）：精神分裂症是一种病因复杂的严重神经精神疾病，影响约1%的人口。目前迫切需要了解这种疾病的潜在病因和病理生理学，以促进新疗法的发展，特别是针对认知功能障碍。最近的全基因组关联和基于家庭的研究已经确定了与精神分裂症相关的几种拷贝数变异（CNVs）。然而，尽管与这些cnv相关的精神分裂症的遗传风险很高，但这些基因组间隔中的病因学相关基因仍然未知。因此，迫切需要系统和可扩展的策略来深入了解与精神分裂症以及其他神经精神疾病相关的基因功能。我们当前应用的总体目标是验证精神分裂症CNVs中特定基因的功能丧失导致调节神经可塑性机制功能障碍的假设。为了验证这一假设，我们的提议有三个目的：1。我们将设计强大的，高通量的，基于图像的神经可塑性分析以及集成的图像分析框架。2. 我们将对精神分裂症基因进行高通量、慢病毒短发夹RNA （shRNA）筛选，以确定神经可塑性的调节因子。3. 我们将通过对候选shrna进行更详细、更高分辨率的形态学和功能分析，以及对培养神经元和脑切片中基础和诱发突触传递的测量，来验证精神分裂症基因的功能缺失细胞和突触表型。我们希望本应用程序中提出的实验将有助于更好地理解神经可塑性的分子和细胞机制，并最终有助于阐明精神分裂症的病因和病理生理学。本提案旨在设计创新策略来评估神经系统中基因的功能，并定义神经元在发育过程中适应变化和响应外部刺激的机制。一旦我们的实验目标实现，我们的长期目标是将类似的策略应用于其他严重的精神障碍，以促进我们对其原因的理解，并为发现改善精神健康的新型药物做出贡献。

DESCRIPTION (provided by applicant): Schizophrenia is a severe neuropsychiatric disorder with complex etiology that affects approximately 1% of the human population. There exists a critical need to understand the underlying etiology and pathophysiology of the disease in order to advance the development of novel therapeutics, particularly to target cognitive dysfunction. Recent genome-wide association and family-based studies have identified several copy number variants (CNVs) associated with schizophrenia. However, despite the strong genetic risk for schizophrenia associated with these CNVs, the etiologically relevant gene(s) in each of these genomic intervals remain unknown. There is therefore a pressing need for systematic and scalable strategies to gain insight into the function of genes associated with schizophrenia as well as other neuropsychiatric disorders. The overall goal of our current application is test the hypothesis that loss-of-function of specific genes within schizophrenia CNVs leads to a dysfunction in mechanisms regulating neuroplasticity. To test this hypothesis our proposal has 3 aims: 1. We will devise robust, high-throughput, image-based assays of neuroplasticity along with an integrated image analysis framework. 2. We will perform high-throughput, lentiviral short hairpin RNA (shRNA) screens of schizophrenia genes to identify regulators of neuroplasticity. 3. We will validate loss-of-function cellular and synaptic phenotypes of schizophrenia genes by performing more detailed, and higher resolution, morphological and functional analyses of candidate shRNAs using imaging and measures of basal and evoked synaptic transmission in cultured neurons and brain slices. It is our hope that the experiments proposed in this application will contribute to gaining a better understanding of the molecular and cellular mechanisms of neuroplasticity and ultimately help illuminate the etiology and pathophysiology of schizophrenia. This proposal seeks to devise innovative strategies for assessing the function of genes in the nervous system and to define the mechanisms through which neurons adapt to changes during development and in response to external stimuli. Once our experimental aims have been achieved, it is our long-term goal to apply similar strategies to other severe mental disorders in order to advance our understanding of their causes and to contribute to the discovery of new types of medicines for improving mental health.