Altered Hippocampal Neurogenesis and Cognition via Maneb-mediated Changes in the Thiol Redox Proteome.

通过代森锰介导的硫醇氧化还原蛋白质组变化改变海马神经发生和认知。

基本信息

批准号：
10113616
负责人：
James R Roede
金额：
$ 38.02万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-03-01 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10113616
关键词：
Affect Age Aging Alzheimer like pathology Alzheimer&apos s Disease Americas Amyloid beta-Protein Precursor Antifungal Agents Behavioral Cell Survival Cells Cellular Stress Cessation of life Chromosome 21 Cognition Cognitive Cognitive deficits Colorado Complex Core Facility Data Disease Down Syndrome Environment Environmental Exposure Exhibits Fibroblasts Food Gene Expression Gene Proteins Genes Genetic Genetic Diseases Genome Goals Health Hippocampus (Brain)Human Imaging Techniques Impaired cognition Impairment Individual Induced pluripotent stem cell derived neurons Induction of Apoptosis Industrial fungicide Industry Institutes Intellectual functioning disability Intervention Isotopically-Coded Affinity Tagging Learning Length Link Live Birth Maneb Mediating Memory Metabolic Pathway Metals Methods Mitochondria Modeling Nerve Degeneration Neurites Neurodegenerative Disorders Neuronal Differentiation Neurons Oxidants Oxidation-Reduction Oxidative Stress Pathway interactions Patients Phenotype Plant Roots Plants Plasma Play Poison Population Predisposition Prevention Process Production Proteome Proteomics Publishing Reactive Oxygen Species Reporting Resources Role Rubber Signal Transduction Stress Sulfhydryl Compounds System Testing Time Tissues Toxic effect Toxicology Transgenic Mice United States Universities Vulnerable Populations Water Xenobiotics age related amyloid pathology base cognitive function design endoplasmic reticulum stress in vivo induced pluripotent stem cell mitochondrial dysfunction mouse model nerve stem cell neurogenesis patient population stem cells theories toxicant transgenic model of alzheimer disease

项目摘要

Abstract The overall goal of this proposal is to elucidate the thiol redox mechanisms that increase xenobiotic toxicity, alter neurite outgrowth, and enhance neurodegeneration. The thiol redox proteome is the adaptive interface between the genome and exposome, providing a means to sense, avoid, and defend against oxidants and other toxicants. Disruption of cellular thiol redox systems, e.g. thiol redox proteome, is a key feature of oxidative stress, contributing to age-related diseases, including neurodegeneration. Enhanced reactive oxygen species (ROS) production in a variety of conditions is linked to mitochondrial dysfunction. Thus, genetic factors or disease processes that cause increased basal levels of stress may result in increased susceptibility of certain populations to environmental exposures. Our preliminary data indicate that individuals with Down syndrome (DS) may be sensitive to the toxic effects of xenobiotics due to their enhanced basal levels of stress. DS is the most common genetic form intellectual disability and the cognitive phenotype can be highly variable. This variability cannot be completely explained by genetics. Additionally, due to a triplication of the amyloid precursor protein gene (APP), all DS patients develop Alzheimer's-like pathology. Based upon preliminary data and published reports, it is hypothesized that environmental exposures contribute to cognitive phenotype variability via disrupted thiol redox signaling and control due to enhanced basal levels of cellular stress and mitochondrial dysfunction. Because ER and oxidative stress are fundamental mechanisms of neurodegeneration, this proposal will investigate the role of redox signaling in the effects of MB on stem cells derived from DS patients, how these exposures affect neurite outgrowth, and how cognitive function is altered in a transgenic mouse model of DS. In Specific Aim 1, we will elucidate the mechanisms of enhanced MB toxicity in DS. Specifically, we will study the roles that oxidative stress, ER stress and mitochondrial dysfunction play in MB-mediated toxicity in DS. In Specific Aim 2, we will utilize iPS cell-derived neural progenitor cells and mature neurons from DS patients and euploid controls to evaluate disease- and toxicant- mediated changes in neurite outgrowth using high-content imaging techniques. Interventions will also be employed to investigate the impact of oxidative stress and ER stress on neurite outgrowth. Alterations in neuronal thiol redox proteome will also be determined using isotope-coded affinity tag (ICAT) redox proteomics. Lastly, in Specific Aim 3 an in vivo mouse model of DS, Dp(16)1Yey/+, will be used to determine the influence of DS and MB exposure on cognitive function. This aim will also characterize MB-mediated neurodegeneration of the hippocampus, and elucidates redox sensitive pathways altered in the hippocampus that impair learning and memory via ICAT redox proteomics. Successful completion of these aims will provide a mechanistic understanding of the role of ER stress, cellular redox status, and the thiol redox proteome in cognition and neurodegeneration.

抽象的该提案的总体目标是阐明增加外源毒性的硫醇氧化还原机制，改变神经突的生长，并加剧神经变性。硫醇氧化还原蛋白质组是适应性接口基因组和暴露体之间，提供了一种感知、避免和防御氧化剂的方法其他有毒物质。细胞硫醇氧化还原系统的破坏，例如硫醇氧化还原蛋白质组，是一个关键特征氧化应激会导致与年龄相关的疾病，包括神经退行性疾病。增强活性氧多种条件下活性氧（ROS）的产生与线粒体功能障碍有关。因此，遗传因素或导致基础压力水平增加的疾病过程可能会导致对以下因素的易感性增加：某些人群暴露于环境。我们的初步数据表明，患有唐氏病的人综合征（DS）可能对异生素的毒性作用敏感，因为它们的基础应激水平较高。 DS 是最常见的遗传形式智力障碍，认知表型变化很大。这种变异性不能完全用遗传学来解释。此外，由于淀粉样蛋白的三倍化前体蛋白基因（APP），所有 DS 患者都会出现类似阿尔茨海默病的病理。根据初步数据和发表的报告中，假设环境暴露有助于认知表型由于细胞应激和基础水平增强，硫醇氧化还原信号和控制受到破坏，从而产生变异性线粒体功能障碍。因为 ER 和氧化应激是神经退行性疾病，该提案将研究氧化还原信号在 MB 对干细胞的影响中的作用来自 DS 患者的数据，这些暴露如何影响神经突生长，以及认知功能如何改变在 DS 转基因小鼠模型中。在具体目标1中，我们将阐明增强MB的机制 DS 中的毒性。具体来说，我们将研究氧化应激、内质网应激和线粒体的作用功能障碍在 DS 中 MB 介导的毒性中发挥作用。在具体目标 2 中，我们将利用 iPS 细胞衍生的神经网络来自 DS 患者和整倍体对照的祖细胞和成熟神经元，以评估疾病和毒物使用高内涵成像技术介导神经突生长的变化。干预措施也将用于研究氧化应激和内质网应激对神经突生长的影响。改动于神经元硫醇氧化还原蛋白质组也将使用同位素编码亲和标签 (ICAT) 氧化还原进行测定蛋白质组学。最后，在特定目标 3 中，将使用 DS 体内小鼠模型 Dp(16)1Yey/+ 来确定 DS 和 MB 暴露对认知功能的影响。这一目标也将表征 MB 介导的海马体的神经变性，并阐明海马体中氧化还原敏感通路的改变通过 ICAT 氧化还原蛋白质组学损害学习和记忆。成功完成这些目标将提供对内质网应激、细胞氧化还原状态和硫醇氧化还原蛋白质组的作用的机制理解认知和神经退行性疾病。