A novel systems analysis of a synaptic gene network

近几十年来，随着老年人口的增加，阿尔茨海默病（AD）是 迅速成为公共卫生问题。这种疾病会导致记忆力丧失，意识模糊， 影响决策。除了与APP和ApoE4相关的家族性AD病例外， 作为一个危险因素，大多数AD病例的人种学未知。因此，一项重大努力是 旨在确定与AD相关的基因，以开发更好的诊断工具 和新的治疗方法。大多数识别AD标志物、靶点 预测因子和风险因素仍然依赖于全基因组关联研究（GWAS）， 以高成本和高误报率而闻名。相比之下，我们的研究从一个 突触网络的蛋白质所需的决策在果蝇，这是保守的， 苍蝇和人类。这种突触网络由具有DNA结合位点的基因组成， DATI是一种保守的转录因子，允许雌性果蝇接受或拒绝雄性果蝇。 值得注意的是，这个网络中88%的基因存在于人类基因组中，而100%的基因存在于人类基因组中。 这些人类基因也含有DATI结合位点，表明这是一个非常深刻的 保守的基因网络可能对理解高级认知功能具有重要意义。 与这一观点一致，网络中10%的蛋白质与APP相互作用，13%的蛋白质与APP相互作用。 AGORA中列出的AD候选基因是该网络的一部分。这些数据一起 强有力地证明这个网络对理解AD很重要。除了 识别这些基因，该项目旨在了解这些基因如何导致 认知功能的出现。为了开始解决这个问题，我们一直在使用 一系列工具来分析完整大脑中3D空间的多维数据。这些工具允许 我们在荧光标记的神经元中分析， 使用地理信息修改网络中其他基因的水平和位置 系统.这一行政补充请求将部分支持购置新的 使用Zeiss LSM900共聚焦显微镜，使用Airyscan 2。在很大程度上， 这些分析的通量取决于共焦显微镜的扫描速度， 所需的分辨率、灵敏度和过程中的自动化。我们预计此次收购 这一新的紧凑型共焦系统将使我们能够提高吞吐量和分辨率， 我们的分析，最终增加我们的研究的影响。

With the increase of the elderly population in recent decades, Alzheimer's disease (AD) is quickly becoming a public health concern. The disease causes loss of memory, confusion and affects decision-making. With the few exceptions of familial AD cases linked to APP and ApoE4 as a risk factor, most AD cases have unknown ethiology. Therefore, a major effort has been directed to identify genes associated with AD with the goal of developing better diagnostic tools and new therapies for the disease. The majority of the strategies to identify AD markers, targets, predictors and risk factors still rely on Genome Wide Association Studies (GWAS), which are known for high costs and a high rate of false positives. In contrast, our study starts with a synaptic network of proteins required for decision-making in Drosophila, which is conserved in flies and in humans. This synaptic network is composed of genes that have DNA binding sites of DATI, a conserved transcription factor that allows female flies to either accept or reject males. Remarkably, 88% of the genes in this network are present in the human genome and 100% of these human genes also contain DATI binding sites, indicating that this is a very deeply conserved gene network likely to be of significance to understand higher cognitive functions. Consistent with this view, 10% of the proteins of the network interact with APP and 13% of the genes listed in AGORA as candidates for AD are part of this network. Together, these data make a strong case that this network is significant for understanding AD. In addition to identifying these genes, this project seeks to understand how these genes lead to the emergence of cognitive functions. To begin addressing this question, we have been using a series of tools to analyze multidimensional data in 3D space in intact brains. These tools allow us to analyze in fluorescently labeled neurons how the knockdown of a gene of the network modifies the levels and localization of other genes of the network using Geographic Information Systems. This administrative supplement request will partially support the acquisition of a new instrument, the Zeiss LSM900 confocal microscope with Airyscan 2. To a significant extent, the throughput of these analyses depends on the scanning speed of the confocal microscope, the resolution required, the sensitivity and automation in the process. We expect that the acquisition of this new compact confocal system will allow us to increase the throughput and resolution of our analyses, ultimately increasing the impact of our study.