The Nerve Terminal as the Site of Action for Type-2 Alkenes

神经末梢作为 2 型烯烃的作用位点

• 批准号: 7531572
• 负责人: Richard Michael Lopachin
• 金额: $ 30.01万
• 依托单位: MONTEFIORE MEDICAL CENTER (BRONX, NY)
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-15 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7531572
• 关键词: Acids; Acrolein; Acrylamide; Acrylamides; Agriculture; Alkenes; Alzheimer' s Disease; Binding; Biological; Brain; Brain Injuries; Carbon; Cell physiology; Cells; Chemicals; Chronic; Class; Condition; Cyclic GMP; Cysteine; Data; Development; Disease; Disruption; Environmental Exposure; Environmental Pollutants; Exposure to; Figs - dietary; Functional disorder; Funding; Gait abnormality; Gene Expression; Generations; Goals; Guanylate Cyclase; Hepatocyte; Human; Ketones; Kidney; Laboratory Animals; Lead; Link; Liver; Measures; Mediating; Molecular; Muscle Weakness; Nerve; Nerve Degeneration; Nerve Tissue; Neuroglia; Neurons; Nitric Oxide; Nitric Oxide Synthase; Nitrites; Oxidative Stress; Pathogenesis; Pathway interactions; Peptides; Peripheral Nervous System Diseases; Pharmacologic Substance; Physiological Processes; Process; Production; Protein Sequence Analysis; Proteins; Proteome; Proteomics; Public Health; Rate; Rattus; Research; Research Design; Research Project Grants; Risk; Signal Transduction; Site; Site-Directed Mutagenesis; Source; Specificity; Sulfhydryl Compounds; Synaptic Vesicles; Synaptosomes; System; Testing; Therapeutic; Thinking; Toxic Environmental Substances; Toxic effect; Toxicant exposure; Toxicokinetics; Triad Acrylic Resin; abstracting; adduct; base; body system; brain cell; cell injury; chemical addition; cigarette smoking; exhaust; exposed human population; indexing; insight; member; methyl acrylate; neuronal cell body; neurotoxicity; neurotransmission; presynaptic; receptor

DESCRIPTION (provided by applicant): Abstract Exposure of humans and laboratory animals to acrylamide (ACR) produces cumulative neurotoxicity characterized by gait abnormalities, muscle weakness and a central-peripheral neuropathy. ACR is an 1,2-unsaturated carbonyl derivative and is classified as a type-2 alkene. This is a large class of electrophilic chemicals that have broad industrial, agricultural and pharmaceutical uses. These chemicals are also well-recognized dietary contaminants and environmental pollutants. Data collected during yrs. 17-20 have provided evidence that ACR impairs nerve terminal function by forming irreversible covalent adducts with nucleophilic sulfhydryl groups on functionally important proteins. Proteomic analyses indicate that the protein targets of ACR and the type-2 alkenes are also acceptors for nitric oxide (NO) signaling. NO is a biological electrophile and has been classically thought to influence cell processes through guanylyl cyclase activation. However, NO can also modulate cell physiology by forming reversible adducts with cysteine thiolates in protein catalytic triads. At the nerve terminal, NO signaling is critically involved in neurotransmission through modulation of the synaptic vesicle cycle and other presynaptic processes. Thus, NO and ACR interact at common cysteine sulfhydryl sites and, therefore, we hypothesize that irreversible adduction of these receptors by ACR blocks reversible NO binding. The disruption of NO signaling and ensuing loss of neuromodulatory control produces presynaptic toxicity. Therefore, Specific Aim #1 research will define the interactions of ACR with the S-nitrosylated (SNO) proteome of CNS nerve terminals. SNOSID (S-nitrosylated site identification) proteomic analysis will be used to demonstrate ACR adduction of SNO-cysteine sites on nerve terminal proteins. Specific Aim #2 studies will evaluate the specificity of the ACR-NO interaction by considering alternative mechanisms of action; i.e., we will determine the effects of ACR on soluble quanylyl cyclase and nitric oxide synthase (NOS) activity/gene expression. Because NO modulates physiological processes in most cells, it is unclear why nerve terminal NO signaling might be selectively targeted by ACR. Therefore, Specific Aim #3 studies will consider several anatomical and molecular features that might predispose nerve terminals to electrophilic attack. Identifying the mechanism of ACR neurotoxicity could offer global insight regarding the toxicological processes of other type-2 alkenes. Results of the proposed research could also help us understand the pathogenesis of Alzheimer's disease (AD) and other chronic neurodegenerative conditions that presumably involve cellular oxidative stress and endogenous generation of acrolein and other type-2 alkenes. PUBLIC HEALTH RELEVANCE Human exposure to conjugated type-2 alkenes (e.g., acrylamide, methyl acrylate, methylvinyl ketone) occurs through pervasive environmental sources (e.g., industrial exposure, cigarette smoking, car exhaust, combustion, pharmaceuticals) and can result in significant toxicity in nervous tissue and other organ systems (liver, kidney). There is also evidence that endogenous production of type-2 alkenes (e.g., acrolein, 2-hydryoxy-4-nonenal) is critically involved in mediating nerve cell injury associated with accidental neurotrauma and certain human neurodegenerative conditions such as Alzheimer's disease. Therefore, the proposed studies of type-2 alkene neurotoxicity could lead to a better understanding of brain injuries caused by environmental toxicant exposure or disease processes, which would ultimately help in the development of effective therapeutic approaches.

描述（由申请人提供）：人类和实验动物对丙烯酰胺（ACR）的抽象暴露会产生累积的神经毒性，其特征在于步态异常，肌肉无力和中央神经病。 ACR是一种1,2不饱和的羰基衍生物，被归类为2型烯烃。这是一大类具有宽阔工业，农业和药物用途的亲电化学物质。这些化学物质也是公认的饮食污染物和环境污染物。在一年期间收集的数据。 17-20提供了证据表明，ACR通过在功能重要的蛋白质上与亲核硫基团形成不可逆的共价加合物来损害神经终末功能。蛋白质组学分析表明，ACR和2型烷烃的蛋白质靶标也是一氧化氮（NO）信号传导的受体。 NO是一种生物学的电力，经过经典的认为可以通过鸟叶兰氏酶激活影响细胞过程。但是，NO还可以通过在蛋白质催化三合会中用半胱氨酸硫醇酯的可逆加合物来调节细胞生理。在神经末端，通过调节突触囊泡循环和其他突触前过程，没有信号传导与神经递质有关。因此，NO和ACR在常见的半胱氨酸亚硫赖尔位点相互作用，因此，我们假设通过ACR块可逆的无结合对这些受体的不可逆转内收。无信号传导和随之而来的神经调节控制丧失的破坏会产生突触前毒性。因此，具体的目标＃1研究将定义ACR与CNS神经末端的S-亚硝基化（SNO）蛋白质组的相互作用。 SNOSID（S-亚硝基化位点识别）蛋白质组学分析将用于证明神经末端蛋白上的SNO-半胱氨酸位点的ACR内收。特定目标2研究将通过考虑替代作用机制来评估ACR-NO相互作用的特异性；也就是说，我们将确定ACR对可溶性丙烯酸糖环酶和一氧化氮合酶（NOS）活性/基因表达的影响。由于没有调节大多数细胞中的生理过程，因此尚不清楚为什么神经终端没有信号被ACR选择性靶向。因此，特定的目标＃3研究将考虑几种解剖学和分子特征，这些特征可能使神经末端易于亲电攻击。确定ACR神经毒性的机制可以为其他2型烷烃的毒理学过程提供全球见解。拟议的研究的结果还可以帮助我们了解阿尔茨海默氏病（AD）的发病机理和其他慢性神经退行性疾病，这些疾病可能涉及细胞氧化应激以及丙烯醛和其他2型烯烃的内源性产生。公共卫生相关性通过普遍的环境来源（例如，工业暴露，吸烟，汽车吸烟，燃烧，燃烧，药物，药物）和其他在神经组织（其他机构）（其他机构）（axprice narkne）（Firfive）（liver）（Firfive）（liver facke），公共卫生接触了共轭类型2型烷烃（例如，丙烯酰胺，丙烯酸甲酯，甲基乙基酮），发生在神经组织和其他机构（其他机构）中（Firfive），这是通过普遍的环境来源（例如工业暴露，吸烟，燃烧，燃烧，燃烧，燃烧，燃烧）。也有证据表明，内源性2型烷烃（例如丙烯醛，2-羟基氧基-4-非纳尔盐）的内源性产生与意外神经疾病和某些人类神经退行性疾病（如阿尔茨海默氏病）的神经细胞损伤有关。因此，对2型烯烃神经毒性的拟议研究可能会更好地理解由环境有毒物质暴露或疾病过程引起的脑损伤，这最终将有助于开发有效的治疗方法。