Oxidative stress and neurogenetic networks in Drosophila

果蝇的氧化应激和神经发生网络

• 批准号: 7819841
• 负责人: Robert R. H Anholt
• 金额: $ 36万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-28 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7819841
• 关键词: Adverse effects; Affect; Architecture; Behavior; Behavioral; Biological Assay; Biological Models; Cell physiology; Cells; Cellular Structures; Chemical Exposure; Chemicals; Chronic; DNA Sequence; Detection; Drosophila genus; Drosophila melanogaster; Environment; Environmental Exposure; Environmental Health; Environmental Risk Factor; Epidemiologic Studies; Exposure to; Female; Functional disorder; Gene Expression Regulation; Generations; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Risk; Genome; Genotype; Health; Herbicides; Human; Impairment; Individual; Laboratories; Learning; Locomotion; Longevity; Measurement; Measures; Medicine; Metabolism; Modeling; Motor Activity; National Human Genome Research Institute; Nerve Degeneration; Network-based; Neurodegenerative Disorders; Orthologous Gene; Oxidative Stress; Paraquat; Parkinson Disease; Pathway interactions; Pattern; Pesticides; Phenotype; Phylogenetic Analysis; Polymorphic Microsatellite Marker; Population; Recruitment Activity; Residual state; Risk Factors; Stress; Toxic Environmental Substances; Transcript; Variant; college; disorder prevention; environmental chemical; genome sequencing; genome wide association study; genome-wide; insight; male; neurogenetics; neuron loss; novel; research study; response; sex; stressor

DESCRIPTION (provided by applicant): Oxidative stress resulting from chemical exposure has been implicated as a contributing risk factor for a range of neurodegenerative diseases. However, it has been challenging to dissect genetic and environmental contributions to phenotypes that are difficult to quantify in genetically heterogeneous human populations, where it is also virtually impossible to control environmental exposure. Drosophila melanogaster provides a genetically tractable model system, because the genetic background and environmental conditions can be precisely controlled, the response to oxidative stressors, such as paraquat, can be measured precisely, and a range of locomotor behaviors can be quantified accurately by simple assays as spontaneous activity patterns, startle-induced locomotor reactivity, and climbing behavior. The objective of this proposal is to delineate the impact of chemically induced oxidative stress on genetic networks that are associated with locomotion phenotypes. The specific aims of this application are: (1) To identify perturbations of genetic networks that are associated with locomotor behaviors by chemically induced oxidative stress; and, (2) To identify DNA sequence variants associated with the effects of oxidative stress on locomotor behaviors in 192 inbred wild-derived lines with fully sequenced genomes. We will capitalize on natural variation in inbred wild-derived lines of Drosophila to construct genome-wide networks of covariant transcripts that are associated with locomotion phenotypes under control conditions and after chronic exposure to paraquat at a concentration that is not acutely lethal, but shortens lifespan. In addition we propose to associate DNA sequence variants in 192 inbred wild-derived Drosophila lines with fully sequenced genomes with variation in these behavioral phenotypes under control conditions and after paraquat exposure. These experiments will generate directional networks for each behavioral phenotype that will enable us to determine to what extent these networks respond to paraquat-induced oxidative stress. We will obtain information about the cellular processes represented by transcripts in these networks and their connectivity, and we will be able to provide functional context for un-annotated transcripts. Comparisons among the control and treatment condition will enable us to evaluate genotype by environment effects at the level of genetic networks and identify critical genes that drive the connectivity of the network under conditions of chemically- induced oxidative stress. Both the mechanisms by which cells respond to oxidative stress and by which oxidative stress leads to cellular damage are likely to show extensive phylogenetic conservation. Thus, superposition of human orthologs on the genetic networks that are associated with behavioral sensitivity to oxidative stress in Drosophila may reveal new universal pathways by which cells adapt to chemical stress or by which chemical stressors affect cell structure, metabolism and function. Such insights will be invaluable for human epidemiological studies on genetic susceptibility to environmental risk factors both by providing a genome-wide perspective of potential adverse effects and by identifying critical genes as potential targets for disease prevention. Health Relevance Environmental toxins, such as the herbicide paraquat, cause neuronal cell death through oxidative stress. Locomotor impairments are sensitive indicators of neurodegeneration. A long- standing challenge in environmental health science is to assess the effects of environmental chemicals such as pesticides or herbicides on genetic risk for neurodegenerative diseases as manifest through locomotor dysfunction (e.g. Parkinson's disease). Studies on genotype by environment interactions require a model system in which both the genetic background and the rearing environment can be controlled precisely. The fruit fly, Drosophila melanogaster, provides such a model. In this application we propose to capitalize on natural variation in inbred wild- derived strains of Drosophila to construct genome-wide networks of covariant transcripts that are associated with a range of locomotor phenotypes, including spontaneous activity, startle- induced locomotion, and gravitaxis, under control conditions and after chronic exposure to paraquat at a concentration that is not acutely lethal, but shortens lifespan. In addition we propose to associate DNA sequence variants in 192 inbred wild-derived Drosophila lines with fully sequenced genomes with variation in these behavioral phenotypes under control conditions and after paraquat exposure. The combined information from these two approaches will result in networks for each behavioral phenotype, in which direct or indirect regulatory interactions between components can be established. The effect of paraquat on these networks can be analyzed in detail. We will be able to determine to what extent these networks, associated with locomotor behaviors respond to paraquat-induced oxidative stress. We will obtain information about the cellular processes represented by these modules, the connectivity of transcripts within these networks, and the functional context of unannotated transcripts. Comparisons among the control and treatment condition will enable us to evaluate genotype by environment effects at the level of genetic networks and identify critical genes that drive the connectivity of the network under conditions of chemical environmental stress. Both the mechanisms by which cells respond to oxidative stress and by which oxidative stress leads to cellular damage are likely to show extensive phylogenetic conservation. Thus, superposition of human orthologs on the genetic networks that are associated with behavioral sensitivity to oxidative stress in Drosophila may reveal new universal pathways by which cells adapt to chemical stress or by which chemical stressors affect cell structure, metabolism and function. Such insights will be invaluable for human epidemiological studies on genetic susceptibility to environmental risk factors both by providing a genome-wide perspective of potential adverse effects and by identifying critical genes as potential targets for disease prevention.

描述（由申请人提供）： 化学暴露引起的氧化应激被认为是一系列神经退行性疾病的危险因素。然而，剖析遗传和环境对表型的贡献一直是一项挑战，这些贡献在遗传异质的人群中很难量化，而且几乎不可能控制环境暴露。黑腹果蝇提供了一个遗传上易于处理的模型系统，因为可以精确控制遗传背景和环境条件，可以精确测量对氧化应激源（如百草枯）的反应，并且可以通过简单的测定准确量化一系列运动行为，如自发活动模式、惊吓引起的运动反应性和攀爬行为。该提案的目的是描述化学诱导的氧化应激对与运动表型相关的遗传网络的影响。该应用的具体目标是：（1）识别与化学诱导的氧化应激导致的运动行为相关的遗传网络的扰动； (2) 鉴定与氧化应激对 192 个具有完全测序基因组的野生近交系运动行为影响相关的 DNA 序列变异。我们将利用果蝇近交野生系的自然变异来构建全基因组的协变转录本网络，这些转录本与控制条件下以及长期接触浓度不严重致死但会缩短寿命的百草枯后的运动表型相关。此外，我们建议将 192 个近交野生果蝇品系中具有完全测序基因组的 DNA 序列变异与对照条件下和百草枯暴露后这些行为表型的变异联系起来。这些实验将为每种行为表型生成定向网络，使我们能够确定这些网络对百草枯诱导的氧化应激的反应程度。我们将获得有关这些网络中的转录本及其连接性所代表的细胞过程的信息，并且我们将能够为未注释的转录本提供功能上下文。对照和处理条件之间的比较将使我们能够在遗传网络水平上评估环境影响的基因型，并识别在化学诱导的氧化应激条件下驱动网络连接的关键基因。细胞响应氧化应激的机制以及氧化应激导致细胞损伤的机制都可能表现出广泛的系统发育保守性。因此，人类直系同源物在与果蝇氧化应激行为敏感性相关的遗传网络上的叠加可能揭示细胞适应化学应激或化学应激物影响细胞结构、代谢和功能的新通用途径。这些见解对于人类流行病学研究对环境风险因素的遗传易感性具有无价的价值，既提供潜在不利影响的全基因组视角，又确定关键基因作为疾病预防的潜在目标。健康相关性 环境毒素，例如除草剂百草枯，会通过氧化应激导致神经细胞死亡。运动障碍是神经退行性变的敏感指标。环境健康科学中的一个长期挑战是评估杀虫剂或除草剂等环境化学物质对神经退行性疾病遗传风险的影响，神经退行性疾病通过运动功能障碍（例如帕金森病）表现出来。通过环境相互作用研究基因型需要一个可以精确控制遗传背景和饲养环境的模型系统。果蝇（Drosophila melanogaster）提供了这样一个模型。在本申请中，我们建议利用近交野生果蝇品系的自然变异来构建全基因组的协变转录本网络，这些转录本与一系列运动表型相关，包括自发活动、惊吓诱导的运动和重力作用，在控制条件下以及在长期暴露于浓度不严重致死但会缩短寿命的百草枯后。此外，我们建议将 192 个近交野生果蝇品系中具有完全测序基因组的 DNA 序列变异与对照条件下和百草枯暴露后这些行为表型的变异联系起来。这两种方法的综合信息将产生每种行为表型的网络，其中可以建立组件之间的直接或间接调节相互作用。可以详细分析百草枯对这些网络的影响。我们将能够确定这些与运动行为相关的网络对百草枯诱导的氧化应激的反应程度。我们将获得有关这些模块所代表的细胞过程、这些网络内转录本的连接性以及未注释转录本的功能上下文的信息。对照和处理条件之间的比较将使我们能够在遗传网络水平上评估环境影响的基因型，并识别在化学环境胁迫条件下驱动网络连接的关键基因。细胞响应氧化应激的机制以及氧化应激导致细胞损伤的机制都可能表现出广泛的系统发育保守性。因此，人类直系同源物在与果蝇氧化应激行为敏感性相关的遗传网络上的叠加可能揭示细胞适应化学应激或化学应激物影响细胞结构、代谢和功能的新通用途径。这些见解对于人类流行病学研究对环境风险因素的遗传易感性具有无价的价值，既提供潜在不利影响的全基因组视角，又确定关键基因作为疾病预防的潜在目标。