Temporal and spacial gene expression pattern in mycotoxin exposed rat lungs and isolated rat lung cells

我最近的研究表明，住宅潮湿材料上常见的真菌毒素在小鼠肺部引起不同毒代动力学的化合物特异性毒性炎症反应。为什么不同的霉菌毒素暴露会在肺部刺激这些不同的炎症反应，目前还不清楚。这项拟议的工作是一项多学科的真菌学研究，旨在利用体外细胞和体内动物模型解决与暴露于真菌毒素引起的肺部疾病有关的基本概念问题。我的短期目标是洞察炎症介质表达的时间和空间模式，并帮助我们理解真菌毒素暴露引起的肺部疾病发病。它也是为了满足我的长期目标，以更好地了解暴露于有毒真菌孢子的肺组织和细胞的一些变化以及与人类接触有关的一些呼吸道症状的基础。提出了一系列实验性的、假设驱动的研究，以确定炎症反应结果中这些差异的机制。利用细胞和/或活体大鼠肺部疾病模型，本研究建议确定a)来自潮湿建筑相关真菌的毒素暴露引起的炎症肺反应的多样性是否是毒素暴露的原代大鼠肺细胞的敏感性和/或炎症介质表达的差异的表现；b)毒素暴露以毒素特异性的方式扰乱肺细胞之间的炎症基因表达和炎症介质的相互作用；c)炎症基因反应和毒物动力学的多样性反映为毒素暴露的大鼠肺组织中炎症基因空间表达的差异。这里提出的使用微阵列和FISH实验代表了一种新的和具有挑战性的方法来解决与霉菌毒素引起的炎症性肺部疾病发病有关的基本的概念性问题。这项工作将促进我们对暴露于真菌毒素引起的肺部疾病的分子机制的理解和新的见解，并促进学生培训，特别是在真菌学、免疫毒理学、实验设计和显微镜方面。

My recent research has revealed that toxins from fungal species common on damp materials in residential housing provoke compound-specific toxic inflammatory responses with different toxicokinetics in mouse lungs. Why different mycotoxin exposures stimulate these diverse inflammatory responses in lungs is unclear. The proposed work is a multidisciplinary mycological investigation designed to address basic, conceptual questions that concern onset of lung disease caused by exposure to fungal toxins using in vitro cell and in vivo animal models. My short-term objective is to provide insight into the temporal and spatial patterns of inflammatory mediator expression, and to aid our understanding of lung disease onset caused by fungal toxin exposures. It is also designed to meet my long-term objective to better understand the basis for the some of changes in lung tissue and cells exposed to toxic fungal spores and some of the respiratory tract symptoms associated with human exposures. A series of experimental, hypothesis-driven studies is proposed to identify mechanisms underlying these differences in inflammatory response outcome. Using cell and/or in vivo rat models of lung disease, the present study proposes to determine whether a) diversity in inflammatory lung responses due to exposure to toxins from damp building associated fungi are a manifestation of differences in the sensitivity and/or inflammatory mediator expression in toxin-exposed primary rat lungs cells, b) toxin exposures perturb inflammatory gene expression and inflammatory mediator interactions amongst lung cells in toxin specific ways, and c) inflammatory gene response and toxicokinetic diversity is reflected as differences in spatial inflammatory gene expression in toxin exposed rat lungs. The use of microarray and FISH experiments proposed herein represents a new and challenging approach to resolve basic, conceptual questions that concern mycotoxin induced inflammatory lung disease onset. The work will advance our understanding of and provide novel insight into molecular mechanisms underlying lung disease caused by exposure to mycotoxins, and promote student training especially in mycology, immunotoxicology, experimental design and microscopy.