权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Novel Mechanisms of Pesticide-Induced Neurotoxicity

农药引起的神经毒性的新机制

基本信息

批准号：
9906057
负责人：
Anumantha Gounder Kanthasamy
金额：
$ 33.37万
依托单位：
IOWA STATE UNIVERSITY
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：
2017-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9906057
关键词：
1-Methyl-4-phenylpyridinium Acetylation Address Animal Disease Models Animal Model Animals Apoptotic Attenuated Autopsy Brain Brain Diseases CREBBP gene Cell Culture Techniques Cell Death Cells ChIP-seq Chronic Complex Data Dieldrin Disease Dopaminergic Cell Dose Environmental Exposure Enzymes Epigenetic Process Etiology Event Exposure to Expression Profiling Functional disorder Gene Expression Genes Goals Histologic Histone Acetylation Histone Deacetylase Histone H3 Histone H4 Histones Homeostasis Human Impairment Link Lysine Maps Mitochondria Modeling Molecular Mus Nerve Degeneration Neurodegenerative Disorders Neurologic Symptoms Neurons Neurotransmitters Oxidative Stress Parkinson Disease Parkinsonian Disorders Pathogenesis Pathway interactions Pattern Pesticides Process Protein Isoforms Proteins Public Health Research Research Proposals Risk Role Rotenone Signal Transduction Site Slice System Time Tissues Transgenic Animals Transgenic Mice Transgenic Organisms Ubiquitin Work brain tissue chromatin remodeling dopaminergic neuron gain of function genome-wide histone acetyltransferase histone modification inhibitor/antagonist knock-down mitochondrial dysfunction mitopark mouse mouse model multicatalytic endopeptidase complex mutant neurochemistry neurotoxic neurotoxicity neurotoxicology nigrostriatal system novel novel strategies pesticide exposure pesticide induced neurotoxicity toxicant

项目摘要

Abstract Environmental exposure to neurotoxic pesticides has been increasingly recognized as a key etiological factor of sporadic Parkinson’s disease (PD). Despite the established link, deciphering the neurotoxicological mechanisms associated with chronic pesticide exposure and its role in the etiopathogenesis of PD has been challenging. Thus, our research proposal intends to explore a novel paradigm in environmental neurotoxicology by studying the acetylation of histone proteins during pesticide exposure using animal models of pesticide neurotoxicity. Among various classes of pesticides, exposure to mitochondria-impairing neurotoxic pesticides, e.g., rotenone, has been linked to the etiology of PD. Mechanistically, exposure to rotenone and another related pesticide, pyridaben, inhibits mitochondrial complex-1 and impairs proteasomal function in neuronal cells. Dopaminergic neurons have been shown to be highly vulnerable to rotenone-induced neurotoxicity. While studying proteasomal dysfunction in mitochondria-impairing pesticide-induced neurotoxicity, we unexpectedly discovered that rotenone- and pyridaben-induced proteasomal inhibition resulted in the accumulation of the major histone acetyltransferase enzyme CBP (CREB-binding protein), which further contributed to acetylation of histones H3 and H4 to promote apoptotic cell death in dopaminergic neurons. Since hyperacetylation of histones is emerging as a key molecular mechanism capable of producing long-term changes in gene expression profiles due to chromatin remodeling, we propose to explore this novel mechanism in the molecular events underlying nigral dopaminergic neuronal damage in chronic mitochondria- impairing pesticide-induced neurotoxicity models. This work will be accomplished by pursuing the following specific objectives: i) Map the hyperacetylation sites of core histones H3 and H4 in dopaminergic neuronal cultures following mitochondria-inhibiting neurotoxic pesticide exposure, ii) Characterize cellular mechanisms of pesticide-induced hyperacetylation of histones H3 and H4 by examining the contributions of various isoforms of histone acetyltransferases (HATs) and histone deacetylases (HDACs), and iii) Determine histone acetylation pattern in chronic rotenone or pyridaben animal models of pesticide neurotoxicity as well as in a progressive mitochondrial dysfunction-induced transgenic mouse model of PD, confirm the changes in acetylation patterns and HAT/HDAC homeostasis in human PD brain tissues, and define the functional significance of histone hyperacetylation-dependent signaling relevant to neurotoxic pesticide-induced neuronal degeneration. Cellular, molecular and neurochemical approaches will be used to delineate these objectives. Collectively, the proposed study represents a novel approach in pesticide neurotoxicological research since the work will provide a comprehensive understanding of the histone hyperacetylation mechanisms pertaining to environmentally- induced nigral dopaminergic neuronal toxicity as it relates to the etiopathogenesis of environmentally-linked PD.

摘要