A novel systems analysis of a synaptic gene network

突触基因网络的新颖系统分析

• 批准号: 10410170
• 负责人: Rui Sousa-Neves
• 金额: $ 25万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10410170
• 关键词: 3-Dimensional; Address; Administrative Supplement; Affect; Alzheimer' s Disease; Amyloid beta-Protein Precursor; Automation; Award; Binding Sites; Brain; Brain imaging; Brain region; Candidate Disease Gene; Cell Death; Complex; Confocal Microscopy; Confusion; DNA Binding; Data; Decision Making; Diagnostic; Disease; Disease Marker; Drosophila genus; Elderly; Female; Gene Expression; Genes; Geographic Information Systems; Goals; Health; Horns; Human; Human Genome; Individual; Label; Lateral; Lead; Link; Lobe; Measurement; Membrane; Memory Loss; Microscope; Modality; Molecular; Neurodegenerative Disorders; Neurons; Odors; Parents; Population; Predictive Factor; Process; Proteins; Public Health; Research; Resolution; Risk Factors; Scanning; Sensory; Series; Spatial Distribution; Speed; Synapses; System; Systems Analysis; apolipoprotein E-4; cholinergic; chromatin remodeling; cognitive function; cost; detector; experimental study; familial Alzheimer disease; fly; genetic variant; genome wide association study; imaging Segmentation; improved; instrument; knock-down; male; multidimensional data; novel; novel therapeutics; olfactory lobe; prevent; receptor; response; segregation; statistics; targeted treatment; tool; transcription factor

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.

近几十年来，随着老年人口的增加，阿尔茨海默病(AD)是 迅速成为一个公共卫生问题。这种疾病会导致记忆力丧失、神志不清和 影响决策。除少数与APP和ApoE4有关的家族性AD病例外 作为一种危险因素，大多数AD病例具有未知的人种学。因此，一项重大努力是 旨在识别与阿尔茨海默病相关的基因，目标是开发更好的诊断工具 以及治疗这种疾病的新疗法。识别AD标记物、靶点、 预测因素和风险因素仍然依赖于基因组广泛关联研究(GWAS)，这些研究包括 以高成本和高误检率而闻名。相比之下，我们的研究始于一个 果蝇决策所需的突触蛋白质网络，它在 苍蝇和人类。这个突触网络由具有DNA结合位点的基因组成 DATI，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 这些人类基因还含有DATI结合位点，表明这是一种非常深刻的 保守的基因网络可能对理解高等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 在AGORA中被列为AD候选的基因是这个网络的一部分。总而言之，这些数据 充分证明该网络对于理解AD具有重要意义。除了……之外 识别这些基因，这个项目试图了解这些基因是如何导致 认知功能的出现。为了开始解决这个问题，我们一直在使用 在完整的大脑中分析3D空间中多维数据的一系列工具。这些工具允许 美国将分析在荧光标记的神经元中如何敲除一个基因的网络 利用地理信息修改网络中其他基因的水平和定位 系统。这一行政补充请求将部分支持收购新的 仪器，蔡司LSM900共焦显微镜和Airyscan2。在很大程度上， 这些分析的吞吐量取决于共聚焦显微镜的扫描速度， 所需的分辨率、过程中的敏感性和自动化。我们预计此次收购 这一新的紧凑型共聚焦系统将使我们能够提高吞吐量和分辨率 我们的分析，最终增加了我们研究的影响。