Environment and Gene Effects on Brain and Behavior

环境和基因对大脑和行为的影响

基本信息

批准号：
7812353
负责人：
JAY S SCHNEIDER
金额：
$ 86.76万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-23 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7812353
关键词：
Acute Affect Alzheimer&apos s Disease Animal Feed Animals Astrocytes Attention deficit hyperactivity disorder Autistic Disorder Behavior Behavior Disorders Behavioral Binding Bioinformatics Biological Markers Brain Brain Chemistry Brain region Candidate Disease Gene Cell membrane Child Chronic Classification Clinical Cognitive Controlled Study CpG dinucleotide DNA Methylation DNA Modification Process DNA Sequence DNA-Binding Proteins Data Databases Development Developmental Gene Diet Disease Disease Outcome Dose Environment Epidemiology Epigenetic Process Exposure to Female Frequencies Functional disorder Gender Gene Expression Gene Expression Profile Gene Expression Profiling Gene Expression Regulation Gene Proteins Genes Genetic Genetic Polymorphism Genetic Variation Genome Genotype Geography Goals Grant Hemochromatosis Hippocampus (Brain)Hispanics Histone Deacetylase Housing Human Immune System Diseases Impairment Individual Intoxication Kidney Diseases Laboratories Language Lead Lead Poisoning Learning Learning Disabilities Life Malignant Neoplasms Memory Mental Retardation Metabolic Methyl-CpG-Binding Protein 2 Methylation Microarray Analysis Modification Molecular Molecular Profiling Motor Skills N-Methyl-D-Aspartate Receptors Neurodevelopmental Disorder Neurons Neurosciences Neurotoxins Outcome Parents Pathogenicity Pathway interactions Perinatal Phenotype Physiological Processes Play Population Porphobilinogen Synthase Predisposition Proteins Race Rat Strains Rattus Regulatory Pathway Reporting Research Rett Syndrome Role Severities Signal Transduction Socioeconomic Status Structure Surveys Time Toxic Environmental Substances Toxic effect Toxicokinetics Toxicology Toxin Transcriptional Regulation Variant Weaning absorption base blood lead brain behavior cDNA Arrays cardiovascular disorder risk comparative disorder risk environmental enrichment for laboratory animals experience gene environment interaction genome-wide lead acetate lead exposure male molecular marker nervous system development neurochemistry neurotoxicity neurotrophic factor novel parent grant promoter protein expression public health relevance response sex social toxicant uptake

项目摘要

DESCRIPTION (provided by applicant): The effects of lead (Pb) on the developing brain have been studied for decades but there are still gaps in our understanding of how this environmental toxicant influences brain development and function. The modification of Pb's influences on nervous system development and function by genetic background and the manner in which Pb interacts with the genome to produce long-lasting behavioral and other effects are mostly unknown. These research questions are the basis of the parent grant associated with this competitive revision application. However, to more fully understand Pb-genome interactions, effects on the epigenome also need to be studied. In particular, this competitive revision application will focus in general on genome-wide Pb-induced alterations in methylation and in particular, on changes in methylation state and expression of MeCP2 (a DNA binding protein involved in transcriptional regulation of a multitude of genes) and critically involved in neuronal maturation and plasticity as well as a variety of cognitive and behavioral disorders including Rett syndrome, autism, mental retardation, ADHD, and learning disabilities. Since recent studies suggest that environmental toxicants can affect the integrity of the genome through effects on epigenetic mechanisms, the extent to which this occurs with different levels and types of Pb exposure need to be studied. Thus, the research proposed in this application has the following specific aim: Specific Aim. Assess the extent to which different types and levels of developmental lead exposure result in epigenetic influences on DNA methylation and MeCP2 expression/methylation in particular and the extent to which these effects correlate with gender and behavioral outcome. These studies will examine the extent to which different types and levels of lead exposure in male and female animals influence DNA methylation on a genome-wide basis and the extent to which there is aberrant MeCP2 promoter methylation and MeCP2 protein expression in the hippocampus, a brain regions known to be functionally affected by developmental lead exposure. We will then correlate these findings with behavioral outcomes. Our hypothesis is that lead exposure leads to a neurodevelopmental disorder, fundamentally, a disorder of plasticity, related to altered epigenetic gene regulation (i.e., alterations in DNA methylation) and that these effects may vary with gender. PUBLIC HEALTH RELEVANCE: The proposed research will provide new data on the effects of developmental lead exposure on epigenetic modifications (i.e., modifications to genes that do not involve changes in the DNA sequence). Recent reports suggest that environmental toxicants may affect the integrity of the genome and can do so through epigenetic mechanisms. Understanding effects of developmental lead exposure on the epigenome may help to tie together basic, clinical and epidemiological data showing effects on a multitude of diverse physiological processes and outcomes including impairments in neuronal structure and functioning and impairments in cognitive, social, language and motor skills that persist into adulthood.

描述（由申请人提供）：数十年来研究了铅（PB）对发育中的大脑的影响，但我们对这种环境有毒物质如何影响大脑发育和功能的理解仍然存在差距。 PB对神经系统发展和功能的影响通过遗传背景以及PB与基因组相互作用以产生持久行为和其他效应的方式大多是未知的。这些研究问题是与此竞争性修订应用相关的父母赠款的基础。但是，为了更充分了解PB基因组相互作用，还需要研究对表观基因组的影响。特别是，这种具有竞争性修订应用程序一般将集中于全基因组诱导的甲基化的变化，尤其是甲基化状态的变化和MECP2的变化（DNA结合蛋白与多种基因的转录调节有关的DNA结合蛋白），以及与神经元的成熟和可塑性以及各种脑类繁殖式的综合性混合物的批判性涉及的，以及批判性地涉及的脑部综合性，是行为不足的，多动症和学习障碍。由于最近的研究表明，环境有毒物质可以通过对表观遗传机制的影响影响基因组的完整性，因此需要研究以不同水平和类型的PB暴露的程度。因此，本应用程序中提出的研究具有以下特定目的：具体目的。评估不同类型和水平的发育铅暴露的程度会导致对DNA甲基化和MECP2表达/甲基化的表观遗传影响，尤其是这些影响与性别和行为结果相关的程度。这些研究将研究男性和雌性动物的不同类型和水平的铅暴露在多大程度上影响DNA甲基化的基因组，以及在海马中存在异常的MECP2启动子甲基化和MECP2蛋白表达的程度，海马（Hippocampus），Hippocampus，Hippocampus，一个大脑区域，已知的大脑区域受到发育铅的功能影响。然后，我们将将这些发现与行为结果相关联。我们的假设是，铅暴露会导致神经发育障碍，从根本上讲，可塑性疾病，与表观遗传基因调控的改变有关（即DNA甲基化的改变），并且这些作用可能随性别而变化。公共卫生相关性：拟议的研究将提供有关发育铅暴露对表观遗传修饰的影响的新数据（即对不涉及DNA序列变化的基因的修改）。最近的报告表明，环境有毒物质可能会影响基因组的完整性，并可以通过表观遗传机制来做到这一点。理解发育铅暴露对表观基因组的影响可能有助于将基本，临床和流行病学数据联系在一起，显示对多种生理过程和结果的影响，包括神经元结构的损害，以及在崇拜中的认知，社会，语言和运动技能的功能以及功能和影响。