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

我最近的研究表明，来自真菌物种的毒素在住宅潮湿材料中常见，在小鼠肺部引起具有不同毒性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刺激肺部这些不同的炎症反应尚不清楚。拟议的工作是一项多学科真菌学研究，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发病有关的基本概念问题。我的短期目标是深入了解炎症介质表达的时间和空间模式，并帮助我们了解真菌毒素暴露引起的肺部疾病发作。它的设计也是为了满足我的长期目标，即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的基础，以及与人类接触有关的一些呼吸道症状。提出了一系列实验，假设驱动的研究，以确定这些炎症反应结果差异的机制。利用细胞和/或体内大鼠肺部疾病模型，本研究拟确定a)暴露于潮湿建筑相关真菌毒素引起的炎症性肺反应的多样性是否表明暴露于毒素的原代大鼠肺细胞中敏感性和/或炎症介质表达的差异，b)毒素暴露以毒素特异性方式干扰炎症基因表达和炎症介质在肺细胞之间的相互作用。c)炎症基因反应和毒代动力学多样性体现为毒素暴露大鼠肺部炎症基因的空间表达差异。本文提出的微阵列和FISH实验的使用代表了一种新的和具有挑战性的方法来解决有关真菌毒素诱导的炎症性肺病发病的基本概念问题。这项工作将促进我们对真菌毒素暴露引起的肺部疾病的分子机制的理解并提供新的见解，并促进学生在真菌学、免疫毒理学、实验设计和显微镜学方面的培训。

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.