QTL and Microarray Mapping Lead Sensitivity Genes

QTL 和微阵列定位先导敏感性基因

• 批准号: 8040300
• 负责人: Douglas M Ruden
• 金额: $ 39.28万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-24 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8040300
• 关键词: 6 year old; ATP phosphohydrolase; Acute; Adult; Affect; Animal Model; Area; Behavior; Behavioral; Behavioral Genetics; Binding Sites; Biochemical; Biological Assay; Blood; Brain; Calcium; Cell membrane; Cells; Centers for Disease Control and Prevention (U.S.); Child; Chromosomes, Human, Pair 2; Chronic; Cloning; Cognitive; Communities; Complex; Courtship; CpG Islands; Custom; DNA Methylation; DNA Resequencing; Development; Developmental Process; Dose; Drosophila genus; Drosophila melanogaster; Environment; Environmental Pollution; Feasibility Studies; Fertility; Gasoline; Gene Expression; Genes; Genetic; Genome; Genomics; Genotype; Goals; Health Fairs; Heavy Metals; High Prevalence; Human; Human Activities; Hyperactive behavior; Inbreeding; Individual; Investigation; Lead; Lead Poisoning; Longevity; Luciferases; Maps; Metal exposure; Methylation; Modeling; Molecular Target; Motor; Motor Activity; Muscle Fibers; Neonatal; Nerve; Nervous system structure; Neurologic; Neuromuscular Junction; Newsletter; Nucleotides; Oregon; Organism; Outcome; Paint; Phase; Physiological; Poison; Predisposition; Public Health; Quantitative Trait Loci; Recombinants; Recruitment Activity; Regulation; Reporter; Research; Resistance; Risk; Running; Sensory; Single Nucleotide Polymorphism; Site; Speed; Symptoms; Synapses; System; Techniques; Testing; Toxic effect; Toy; Translating; United States; base; blood lead; chronic Pb exposure; cognitive function; design; drinking water; fly; genetic analysis; lead exposure; meetings; metropolitan; neurotoxicity; next generation; research study; response; trait; transcription factor; vector

DESCRIPTION (provided by applicant): Human activity has resulted in the environmental distribution of many toxic substances, among them the heavy metals that are spread throughout our biosphere. In addition to the acute toxic effects to humans exposed to lead (i.e. in lead paint or in contaminated drinking water) there are more insidious effects of chronic exposure on the development of all organisms. Children exposed to low levels of lead have altered developmental processes, and these children develop symptoms such as hyperactivity, changes in sensory function, and changes in cognitive abilities ("IQ"). We have made considerable progress during the first 5 years of this project in using Drosophila as a model organism to study the effects of lead exposure during development by using: (1) the sophisticated under-standing of its genetics, and the ease of manipulating its genome; (2) the availability of behavioral and morphological assays sensitive to small effects of very low doses of lead. There is a great deal of variability in the sensitivity of lead exposure, and both human and Drosophila cells are thought to induce expression of "protective genes" upon exposure to lead. Behavior is an especially sensitive end point of lead-induced neurotoxicity because it is a net result of sensory, motor, and cognitive functions in the nervous system. The hypothesis for this proposal is that one can identify some of the "protective genes" that make an organism resistant to the behavioral and developmental effects of lead toxicity using quantitative trait loci (QTL) mapping techniques combined with microarray and sophisticated genetic analyses. To test this hypothesis, we propose 3 Aims. Aim 1 Identify the genes that affect locomotor activity and gene expression at marker loci 30AB and 50DF. Aim 2 is to identify new QTLs that are involved in calcium conduction at the larval synapse. Aim 3 is to translate our findings from flies to humans exposed to lead from the environment. In this aim, we will determine whether specific CpG site DNA methylation levels correlate with lead levels in blood collected from children in the Detroit metropolitan area. Results of these studies will identify candidates for the most important genes that are altered during lead exposure in humans, and could well lead to bioassays or treatments for heavy metal exposure in humans. PUBLIC HEALTH RELEVANCE: Over 120 million people in the world have blood lead levels of greater than 10 micrograms per deciliter, which is considered the 'safe level' by the Centers for Disease Control. We are continuing a project that uses sophisticated genetics and genomics techniques to understand why some strains of Drosophila are more sensitive to the neurotoxicological effects of lead. In the next 5 year period, we will begin studies to see how lead affects DNA methylation in children with high blood levels and determine the common regulatory mechanisms between Drosophila and humans.

描述（由申请人提供）：人类活动导致许多有毒物质在环境中分布，其中重金属在我们的生物圈中传播。除了对接触铅（即铅涂料或受污染的饮用水）的人类产生急性毒性影响外，慢性接触对所有生物体的发育还有更阴险的影响。接触低水平铅的儿童会改变发育过程，这些儿童会出现多动、感觉功能改变和认知能力（“智商”）改变等症状。在这个项目的前5年里，我们利用果蝇作为模型生物来研究发育过程中铅暴露的影响，通过以下几个方面取得了相当大的进展：(1)对其遗传学的深入了解，以及对其基因组的易于操作；(2)对极低剂量铅的微小影响敏感的行为学和形态学分析的可用性。铅暴露的敏感性有很大的差异，人类和果蝇细胞都被认为在接触铅时诱导“保护基因”的表达。行为是铅诱导的神经毒性的一个特别敏感的终点，因为它是神经系统中感觉、运动和认知功能的净结果。这项提议的假设是，人们可以利用数量性状位点（QTL）定位技术，结合微阵列和复杂的遗传分析，识别出一些“保护基因”，这些基因使生物体抵抗铅毒性的行为和发育影响。为了验证这一假设，我们提出了3个目标。目的1：确定影响运动活动的基因和30AB和50DF标记位点的基因表达。目的2是鉴定幼虫突触中参与钙传导的新qtl。目标3是将我们的发现从苍蝇转化为暴露于环境铅的人类。在这个目的中，我们将确定特定CpG位点DNA甲基化水平是否与从底特律大都会地区儿童收集的血液中的铅水平相关。这些研究的结果将确定在人类铅暴露期间发生改变的最重要基因的候选基因，并很可能导致人类重金属暴露的生物测定或治疗。