A novel systems analysis a synaptic gene network

一种新的系统分析突触基因网络

• 批准号: 9791149
• 负责人: Rui Sousa-Neves
• 金额: $ 40万
• 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/9791149
• 关键词: 3-Dimensional; Affect; Alzheimer' s Disease; Amyloid Beta A4 Precursor Protein; Biological Process; Brain; Cell Death; Cell Volumes; Cells; Cholinergic Receptors; Chromatin; Cognition; Cognitive; Complex; Confusion; Data; Decision Making; Dementia; Dimensions; Disease; Drosophila genus; Elderly; Etiology; Female; Functional disorder; Gene Expression; Gene Expression Regulation; Gene Proteins; Genes; Geographic Information Systems; Growth; Health; Homeostasis; Human; Individual; Invertebrates; Knowledge; Lead; Link; Location; Maintenance; Maps; Memory Loss; Methods; Modeling; Molecular; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Nicotinic Receptors; Orthologous Gene; Outcome; Pattern; Performance; Physical condensation; Population; Process; Public Health; Regulation; Research; Resolution; Risk Factors; Series; Signal Transduction; Synapses; System; Systems Analysis; Systems Biology; Testing; Time; apolipoprotein E-4; base; cholinergic; cholinergic neuron; chromatin remodeling; cognitive ability; cognitive function; cognitive process; data management; experimental study; gene discovery; gene function; genome wide association study; genome-wide; improved; innovation; neuron loss; neuropathology; novel; prevent; protein expression; receptor; spatial relationship; statistics; synaptic depression; targeted treatment; tool; transcription factor

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.

摘要 阿尔茨海默病（Alzheimer's disease，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、思维混乱，并影响决策。所作的努力， 在过去的几十年中，人们鉴定出了一些与AD相关的重要基因。比如说， 5%的AD病例与APP基因相关，20-50%与ApoE 4相关， 其余的则被指定为ApoE 4非携带者和零星AD。ApoE 4是 被认为是一个风险因素。因此，大多数AD病例的病因仍不清楚。这 随着βA调节nAChRα7活性的发现，情况开始改变 通过在低浓度下增强受体活性和在高浓度下抑制受体活性， 高浓度。这些和其他观察结果共同构成了一个强有力的理由，即AD可能 是一种起源于突触功能障碍的疾病然而，这种可能性提出了一个 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，这些网络在不同的 神经元，而不是所有的神经元都致力于认知功能，这使得它非常 很难选择正确的网络并理解其组织和功能。克服 这些障碍，在这里，我们提出了一个系统的方法来识别一个保守的突触内， 认知功能所需的网络，这些组件有效地认知 功能协调发展的我们的初步数据提供了强有力的证据，我们确定的几个基因是部分 在决策过程中所需的胆碱能突触网络与APP或βA相关。 为了了解这些基因的错误调节是如何导致突触功能障碍的，我们提出 一系列的实验使用泡泡地图，一个强大的平台，由我们的小组开发。这 平台允许分析具有单像元分辨率和地理空间分辨率的复杂3D数据 跨多个维度的参考，例如时间、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 第一次实施地理信息系统（GIS），以检索高分辨率 一个复杂的细胞/分子网络的信息。地理信息系统是一个强大的系统， 管理，地图模式分析，空间统计，基于属性的空间定位 查询和建模空间关系。我们希望Aim 1能导致发现小说 这个突触网络的组件有效地需要决策，扩大 一些第二和第三阶互动，并提供了更广泛的网络及其 目标2将验证这些基因的生物学功能，建立调控基因， 它们之间的关系，并定义这些关系如何有助于正确的连接 目标3将测试该网络中的干扰是否会导致 整个大脑内的突触功能障碍和神经元死亡。这项研究计划是针对 对发现涉及突触功能障碍的基因，并预计将增加我们的 了解AD及相关神经退行性疾病的致病因素。 与人类健康的关系 在不断增长的老年人口中，神经退行性疾病，如阿尔茨海默病， 日益成为公共卫生问题。使用系统方法识别 与神经退行性疾病相关的复杂分子网络有可能 发现关键分子参与者，开发靶向治疗，以预防或改善 AD和相关疾病的症状。