Mechanisms of Trichothecene Toxicity

描述(由申请人提供)：毛霉烯是一大类真菌毒素，通常被视为食品污染物，在全球范围内与人类胃肠炎有关，并因其在化学恐怖主义和战争中的潜在用途而受到进一步关注。三氯乙烯和其他核糖体导向的试剂(例如，蓖麻毒素、志贺毒素)激活丝裂原活化蛋白激酶(MAPKs)，通过核毒性应激反应启动炎症基因表达和细胞凋亡，然而，具体的信号转导机制却鲜为人知。本研究的目的是确定模型毛霉烯脱氧雪腐镰刀菌烯醇(DON或“呕吐毒素”)诱导p38MAPK激活的细胞内信号通路和机制，并将其与炎症和细胞凋亡联系起来。我们的中心假设是双链RNA激活蛋白激酶(PKR)和造血细胞激酶(HCK)在三氯乙烯诱导的p38激活和下游毒性中起关键作用。为了验证这一假设，我们的研究小组将使用1)基因敲除小鼠来验证PKR和HCK在p38激活和下游毒性中的作用，以及2)巨噬细胞阐明通过PKR和HCK将DON与p38联系起来的信号转导元件。我们提出了四个具体的目标：1)研究PKR在DON诱导的p38激活和下游毒性效应中的作用；2)表征HCK在DON诱导的p38激活和下游毒性效应中的作用；3)评估核糖体在DON诱导的p38激活中的作用；以及4)评估Toll样受体在DON诱导的p38激活中的作用。该项目将通过以下方式增进公众健康：1)提高对这些三氯乙烯和核毒性化学品如何扰乱肠道免疫的分子理解；2)增强我们评估和管理与接触这些制剂相关的风险的能力；3)制定基于机制的战略，以预防和/或治疗因自然污染或化学恐怖主义/战争而暴露于这些化合物的人的毒性。

DESCRIPTION (provided by applicant): The trichothecenes, a large group of fungal toxins that are commonly encountered as food contaminants, have been etiologically linked to human gastroenteritis worldwide and are of further concern for their potential use in chemical terrorism and warfare. Trichothecenes and other ribosome-directed agents (eg. ricin, shiga toxin) activate mitogen-activated protein kinases (MAPKs) and subsequently initiate inflammatory gene expression and apoptosis via a mechanism known as the "ribotoxic stress response", however, little is known of the specific signal transduction mechanisms involved. The objective of this proposal is to identify the intracellular signaling pathways and mechanisms by which the model trichothecene deoxynivalenol (DON or "vomitoxin") induces p38 MAPK activation and relate these to inflammation and apoptosis. Our central hypothesis is that double stranded RNA-activated protein kinase (PKR) and hematopoietic cell kinase (Hck) are critical for trichothecene-induced p38 activation and downstream toxicity. To test this hypothesis, our research team will use 1) knockout mice to verify roles for PKR and Hck in p38 activation and downstream toxicity and 2) macrophages to elucidate signal transduction elements that link DON to p38 via PKR and Hck. Four specific aims are proposed: 1) Characterize the role of PKR in DONinduced p38 activation and downstream toxic effects; 2) Characterize the role of Hck in DON-induced p38 activation and downstream toxic effects; 3) Assess role of the ribosome in DON-induced p38 activation; and 4) Evaluate role of Toll-like receptors in DON-induced p38 activation. This project will enhance public health by: 1)improving molecular understanding of how these trichothecenes and ribotoxic chemicals disrupt gut immunity, 2) enhancing our capacity to assess and manage risks associated with exposure to these agents and 3) generating mechanism-based strategies for preventing and/or treating toxicity in persons exposed to these compounds via natural contamination or chemical terrorism/warfare.