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

我最近的研究表明，住宅中潮湿材料上常见的真菌毒素在小鼠肺中引起了具有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刺激肺部的这些不同的炎症反应尚不清楚。拟议的工作是一个多学科的真菌学调查，旨在解决基本的，概念性的问题，关注肺部疾病的发病所造成的暴露于真菌毒素使用体外细胞和体内动物模型。我的短期目标是提供炎症介质表达的时间和空间模式的见解，并帮助我们了解真菌毒素暴露引起的肺部疾病发作。它也是为了满足我的长期目标，以更好地了解肺组织和细胞暴露于有毒真菌孢子的一些变化的基础，以及与人类暴露相关的一些呼吸道症状。一系列的实验，假设驱动的研究，提出了确定这些差异的炎症反应结果的机制。使用肺部疾病的细胞和/或体内大鼠模型，本研究提出确定a）由于暴露于来自潮湿建筑物相关真菌的毒素引起的炎性肺反应的多样性是否是暴露于毒素的原代大鼠肺细胞中的敏感性和/或炎性介质表达差异的表现，B）毒素暴露干扰B炎性基因表达和肺细胞中以毒素特异性方式的炎性介质相互作用，和c）炎症基因应答和毒代动力学多样性反映为毒素暴露的大鼠肺中空间炎症基因表达的差异。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作的基本概念问题。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，并提供新的见解，并促进学生的培训，特别是在真菌学，免疫毒理学，实验设计和显微镜。

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.