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Trichothecene Toxicity and the Ribotoxic Stress Response

单端孢菌素毒性和核糖应激反应

基本信息

批准号：
8272657
负责人：
James J Pestka
金额：
$ 30.17万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1984
资助国家：
美国
起止时间：
1984-03-01 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8272657
关键词：
Acute Acute Disease Address Affinity Animals Anisomycin Apoptosis Apoptotic Binding Biological Cell Survival Cells Centers for Disease Control and Prevention (U.S.)Chemicals Chronic Chronic Disease Complement Data Disease Double-Stranded RNA Ensure Environment Enzymes Event Exposure to Food Food Contamination Gene Expression Genetic Transcription Goals Grant Health Human Immune system Immunity Inflammatory Intestines KRP protein Kinetics Knowledge Lead Learning Light Link Lymphoid Tissue MAPK14 gene MAPK8 gene Maps Measures Mediating Messenger RNA Mitogen-Activated Protein Kinases Modeling Molecular Molecular Biology Mononuclear Mus Mycotoxins Outcome Pathway interactions Persons Phagocytes Phosphorylation Phosphotransferases Play Protein Kinase Protein-Serine-Threonine Kinases Proteins Proteomics Proto-Oncogene Proteins c-akt Public Health Publishing Qualifying RNA Recombinants Recommendation Relative (related person)Reporting Research Reticulocytes Ribonucleases Ribosomal RNA Ribosomes Ricin Risk Risk Assessment Risk Management Role Sentinel Shiga Toxin Signal Transduction Site Stress Techniques Terrorism Testing Toxic effect Toxin Translations Trichothecenes Work base biological adaptation to stress deoxynivalenol eIF-2 Kinase foodborne hazard immune function improved innovation insight macrophage monocyte nuclease prevent response scaffold sensor sound stressor success uptake

项目摘要

DESCRIPTION (provided by applicant): The trichothecenes, a group of sesquiterpenoid mycotoxins commonly encountered as food contaminants worldwide, have been etiologically linked to human and animal illnesses with the immune system being a major target. In experimental animals, these mycotoxins and other natural toxins that bind with high affinity to eukaryotic ribosomes (eg. ricin, Shiga toxin, anisomycin) induce proinflammatory gene expression and apoptosis in lymphoid tissues. Because of their potential for use in chemical terrorism, trichothecenes and other ribotoxins are now included on the CDC Select Agents list. Although ribosome-directed agents are known to exert toxicity by activating mitogen-activated protein kinases, the underlying mechanisms for this "ribotoxic stress response" (RSR) remain largely undefined. Thus, a critical gap exists in our knowledge of the signal transduction mechanisms by which ribotoxins modulate gene expression and apoptosis. The objective of this proposal is to test the guiding hypothesis that the ribosome plays a central role in the initiation and integration of protein kinase-mediated stress responses to trichothecenes and other ribotoxic agents. This hypothesis is based on observations in the macrophage that: 1)deoxynivalenol (DON), a common foodborne trichothecene, mediates cleavage of 18S and 28S ribosomal (r)RNA, 2) double-stranded RNA-activated protein kinase (PKR), a ribosome-associated serine-threonine kinase, is essential for DON-induced protein kinase activation and 3) DON induces mobilization of several protein kinases to the ribosome whereupon they are phosphorylated. To test our hypothesis, three Specific Aims are proposed. In Aim 1, we will characterize DON-induced rRNA cleavage relative to targets, kinetics and mechanisms in the macrophage. In Aim 2, we will use both macrophage and cell-free models to characterize the role of PKR as an early sensor of DON-induced rRNA damage. In Aim 3, we will track DON-induced changes in ribosome-associated proteins in the macrophage relative to composition, kinetics and kinase activites. From these studies, we expect to understand how the ribosome mediates the induction and integration of multiple intracellular signaling cascades that drive altered gene expression and apoptosis in mononuclear phagocytes in response to ribotoxic agents. Anticipated outcomes include: 1) improved understanding of the molecular basis by which trichothecenes and other ribotoxins disrupt immunity, 2) enhanced capacity to assess and manage risks associated with exposure to trichothecenes and other ribotoxins, and 3) mechanism-based strategies for preventing and/or treating persons exposed to trichothecenes and ribotoxic chemicals via natural contamination or chemical terrorism. Collectively, these outcomes will positively impact public health by providing a scientific basis for generating sound recommendations relative to this important class of toxins and appropriate remedial actions should exposure occur. PUBLIC HEALTH RELEVANCE: We propose to learn how a class of potent biological toxins interferes with the function and survival of cells that are essential to the immune system. This research will enhance our capacity to assess and manage risks associated with exposure to these toxins as well as yield mechanism-based strategies for preventing and/or treating persons exposed to these agents via inadvertent food contamination or deliberate chemical terrorism. Collectively, these outcomes will positively impact public health by providing a scientific basis for generating sound recommendations relative to these important toxins and appropriate remedial actions should exposures occur.

描述（由申请人提供）：倍半萜烯是一组在世界范围内常见的食品污染物，在病原学上与人类和动物疾病有关，免疫系统是主要靶点。在实验动物中，这些真菌毒素和其他天然毒素以高亲和力结合真核生物核糖体（例如，蓖麻毒素、滋贺毒素、茴香霉素）诱导淋巴组织中促炎基因表达和凋亡。由于它们在化学恐怖主义中的潜在用途，这些毒素和其他核毒素现在被列入CDC的选择药物清单。虽然已知核糖体导向剂通过激活促分裂原活化蛋白激酶来发挥毒性，但这种“核糖毒性应激反应”（RSR）的潜在机制在很大程度上仍不明确。因此，一个关键的差距存在于我们的知识的信号转导机制，核糖毒素调节基因表达和细胞凋亡。本提案的目的是检验指导性假设，即核糖体在蛋白激酶介导的对胞二烯和其他核糖毒性剂的应激反应的起始和整合中起核心作用。该假设基于巨噬细胞中的观察结果：1）脱氧雪腐镰刀菌烯醇（DON），一种常见的食源性雪腐镰刀菌烯，介导18 S和28 S核糖体（r）RNA的切割，2）双链RNA活化蛋白激酶（PKR），一种核糖体相关的丝氨酸-苏氨酸激酶，对于DON诱导的蛋白激酶活化是必需的，以及3）DON诱导几种蛋白激酶向核糖体的移动，在核糖体上它们被磷酸化。为了验证我们的假设，提出了三个具体目标。在目标1中，我们将描述DON诱导的rRNA切割相对于巨噬细胞中的靶点、动力学和机制。在目标2中，我们将使用巨噬细胞和无细胞模型来表征PKR作为DON诱导的rRNA损伤的早期传感器的作用。在目标3中，我们将跟踪DN诱导的核糖体相关蛋白在巨噬细胞中的组成，动力学和激酶活性的变化。从这些研究中，我们期望了解核糖体如何介导多个细胞内信号级联的诱导和整合，这些信号级联驱动单核吞噬细胞对核糖毒性剂的反应中改变基因表达和凋亡。预期成果包括：1）提高对二孢霉素和其他核糖毒素破坏免疫力的分子基础的理解，2）提高评估和管理与接触二孢霉素和其他核糖毒素相关的风险的能力，以及3）预防和/或治疗通过自然污染或化学恐怖主义接触二孢霉素和核糖毒性化学品的人的基于机制的策略。总的来说，这些成果将对公众健康产生积极影响，为就这一重要类别的毒素提出合理建议以及在发生接触时采取适当补救行动提供科学依据。公共卫生相关性：我们建议了解一类有效的生物毒素如何干扰对免疫系统至关重要的细胞的功能和存活。这项研究将提高我们评估和管理与接触这些毒素相关的风险的能力，并产生基于机制的战略，以预防和/或治疗因无意中的食品污染或故意的化学恐怖主义而接触这些物质的人。总的来说，这些成果将对公众健康产生积极影响，为制定与这些重要毒素有关的合理建议和在发生接触时采取适当补救行动提供科学依据。

项目成果

期刊论文数量（78）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Murine Anorectic Response to Deoxynivalenol (Vomitoxin) Is Sex-Dependent.

DOI：
10.3390/toxins7082845
发表时间：
2015-07-29
期刊：
Toxins
影响因子：
4.2
作者：
Clark ES;Flannery BM;Pestka JJ
通讯作者：
Pestka JJ

Targets and intracellular signaling mechanisms for deoxynivalenol-induced ribosomal RNA cleavage.

DOI：
10.1093/toxsci/kfs134
发表时间：
2012-06
期刊：
Toxicological sciences : an official journal of the Society of Toxicology
影响因子：
0
作者：
He K;Zhou HR;Pestka JJ
通讯作者：
Pestka JJ

Comparison of murine anorectic responses to the 8-ketotrichothecenes 3-acetyldeoxynivalenol, 15-acetyldeoxynivalenol, fusarenon X and nivalenol.

DOI：
10.1016/j.fct.2012.03.055
发表时间：
2012-06
期刊：
Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association
影响因子：
0
作者：
Wenda Wu;B. Flannery;Y. Sugita‐Konishi;M. Watanabe;Haibin Zhang;J. Pestka
通讯作者：
Wenda Wu;B. Flannery;Y. Sugita‐Konishi;M. Watanabe;Haibin Zhang;J. Pestka

In vitro effects of vomitoxin (deoxynivalenol) on T-cell interleukin production and IgA secretion.

呕吐毒素（脱氧雪腐镰刀菌烯醇）对 T 细胞白细胞介素生成和 IgA 分泌的体外影响。