Functional Genomics of Neuroplasticity in Schizophrenia

描述(申请人提供)：精神分裂症是一种严重的神经精神疾病，具有复杂的病因，影响大约1%的人口。迫切需要了解该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的治疗。最近的全基因组关联和基于家庭的研究已经确定了几个与精神分裂症相关的拷贝数变异(CNV)。然而，尽管与这些CNV相关的精神分裂症的遗传风险很大，但每个基因组间隔中的致病相关基因(S)仍然未知。因此，迫切需要系统化和可扩展的策略，以深入了解与精神分裂症和其他神经精神障碍相关的基因的功能。我们目前应用的总体目标是检验这一假设，即精神分裂症CNV中特定基因的功能丧失会导致神经可塑性调节机制的功能障碍。为了验证这一假设，我们的建议有三个目标：1.我们将设计健壮的、高通量的、基于图像的神经可塑性分析方法，以及一个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状RNA(ShRNA)筛选，以确定神经可塑性的调节因素。3.我们将通过对候选shRNA进行更详细、更高分辨率的形态和功能分析，以及在培养的神经元和脑片中进行基础和诱发突触传递的成像和测量，来验证精神分裂症基因功能丧失的细胞和突触表型。我们希望本申请中提出的实验将有助于更好地了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。这项提议旨在设计创新的策略来评估神经系统中的基因功能，并确定神经元在发育过程中适应变化和对外部刺激做出反应的机制。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.