A novel systems analysis a synaptic gene network

摘要 阿尔茨海默病(AD)是困扰老年人的最常见疾病之一。 这种疾病会导致记忆力丧失、精神错乱，并影响决策。在中国做出的努力 在过去的几十年里，人们发现了一些与阿尔茨海默病相关的重要基因。例如, 5%的AD病例与APP基因有关，20%-50%与ApoE4和 其余的收到像ApoE4非携带者和零星AD这样的称号。然而，ApoE4是 被认为是一个危险因素。因此，大多数AD病例的病因仍不清楚。这 随着发现βA调节nAChRα7的活动，情况开始改变 烟碱受体在低浓度时增强受体活性，在低浓度时抑制它 浓度很高。这些和其他观察结果一起构成了一个强有力的理由，即AD可能 是一种源于突触功能障碍的疾病。然而，这种可能性构成了一个 问题是因为突触拥有极其复杂的网络，我们仍然有一个有限的 了解其复杂的规则。此外，这些网络在不同方面也是不同的 神经元，并不是所有的神经元都致力于认知功能，这使得 很难选择正确的网络并了解其组织和功能。要克服 这些障碍，在这里，我们提出了一种系统的方法来识别保守的突触 认知功能所需的网络，认知功能有效需要的那些组件 功能。我们的初步数据提供了强有力的证据，我们确认的几个基因是 决策所需的胆碱能突触网络与APP或βA有关。 为了理解这些基因的错误调控如何导致突触功能障碍，我们提出了 使用我们团队开发的功能强大的平台Bubble Maps进行了一系列实验。这 平台允许以单像元分辨率和地理空间分析复杂的3D数据 参考多个维度，如时间、空间位置、基因和蛋白质水平 表达、细胞体积、染色质凝聚等。气泡地图提供了 首次实施地理信息系统(GIS)以检索精细分辨率 复杂的细胞/分子网络的信息。地理信息系统是一种用于数据的健壮系统 管理、地图模式分析、空间统计、使用基于属性的空间定位 查询以及对空间关系进行建模。我们期待着《发现》这部小说的出版 此突触网络的有效决策所需的组件，扩展 二阶和三阶互动体的数量，并提供对网络及其 目标2将验证这些基因的生物学功能，建立调控 它们之间的关系，并定义这些关系如何有助于正确连接 以及这些神经元的表现；目标3将测试这个网络中的干扰是否会导致 整个大脑中的突触功能障碍和神经元死亡。这项研究计划是精心设计的 对涉及突触功能障碍的基因的发现，并有望增加我们的 了解阿尔茨海默病及相关神经退行性疾病的致病因素。 与人类健康的相关性 在不断增长的老年人口中，阿尔茨海默病等神经退行性疾病 日益成为一个公共卫生问题。使用系统方法来识别 与神经退行性疾病相关的复杂分子网络有可能 发现关键的分子参与者并开发有针对性的治疗方法来预防或改善 阿尔茨海默病及相关疾病的情况。

ABSTRACT Alzheimer's disease (AD) is one of the most common diseases that afflict the elder population. The disease causes loss of memory, confusion and affects decision-making. The effort made in past decades led to the identification of some significant genes associated to AD. For example, 5% of the AD cases are associated to the APP gene, 20-50% are associated to ApoE4 and the remaining receive designations like ApoE4 non-carriers and sporadic AD. However, ApoE4 is considered to be a risk factor. Thus, most cases of AD still have an unclear etiology. This scenario began to change with the discovery that βA regulates the activity of the nAChRα7 nicotinic receptor by potentiating the receptor activity at low concentrations and inhibiting it at high concentrations. Together these and other observations make a strong case that AD might be a disease with an origination in synaptic dysfunction. However, that possibility poses a problem because synapses possess extremely complex networks and we still have a limited understanding of their complex regulation. Also, these networks are different in different neurons and not all of them are dedicated to cognitive function, which makes it extremely difficult to select the correct network and understand its organization and function. To overcome these hurdles, here we propose a systems approach to identify within a conserved synaptic network required for cognitive functions, those components effectively required for cognitive functions. Our preliminary data provide strong evidence that several genes we identified as part of a cholinergic synaptic network required in decision-making are associated either APP or βA. To understand how the mis-regulation of these genes leads to synaptic dysfunction we propose a series of experiments using Bubble Maps, a powerful platform developed by our group. This platform allows for analyzing complex 3D data with single cell resolution and geospatial referencing across multiple dimensions such as time, spatial location, levels of gene and protein expression, cell volumes, chromatin condensation, among others. Bubble Maps provides the first implementation of Geographical Information Systems (GIS) to retrieve fine resolution information of a complex cellular/molecular network. GIS is a robust system used for data management, map pattern analyses, spatial statistics, spatial location using attribute-based queries, and modeling spatial relationships. We expect that Aim1 will lead to the discover novel components of this synaptic network effectively required for decision-making, expand the number of second and third order interactors, and provide a broader view of the network and its edges; Aim 2 will validate the biological functions of these genes, establish regulatory relationships between them and define how these relationships contribute to proper connectivity and performance of these neurons; Aim 3 will test if disturbances in this network leads to synaptic dysfunction and neuronal death within entire brains. This research plan is geared toward the discovery of genes involved in synaptic dysfunction and is expected to increase our understanding of causative factors of AD and related neurodegenerative disease. RELEVANCE FOR HUMAN HEALTH In a growing elder population, neurodegenerative diseases such as Alzheimer's Disease, are increasingly becoming a public health concern. The use of systems approach to identify complex molecular networks associated to neurodegenerative disorders holds the potential to uncover key molecular players and develop targeted therapies to prevent or improve the condition of AD and related diseases.