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

霉菌毒素暴露大鼠肺和分离的大鼠肺细胞中的时空基因表达模式

• 批准号: 89667-2007
• 负责人: Rand, Thomas
• 金额: $ 2.06万
• 依托单位: Saint Mary's University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2009
• 资助国家: 加拿大
• 起止时间: 2009-01-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=421552
• 关键词: Temporal; spacial; gene; expression; pattern

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.

我最近的研究表明，住宅潮湿材料上常见的真菌物种的毒素会在小鼠肺部引起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，旨在解决有关使用体外细胞和体内动物模型暴露于真菌毒素引起的肺部疾病的基本概念性问题。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的发病。它还旨在实现我的长期目标，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，以及与人类暴露相关的一些呼吸道症状。提出了一系列实验性、假设驱动的研究来确定炎症反应结果差异背后的机制。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)由于暴露于潮湿建筑相关真菌的毒素而导致的炎症性肺部反应的多样性是否是敏感性和/或炎症介质差异的表现毒素暴露的原代大鼠肺细胞中的表达，b）毒素暴露以毒素特定方式扰乱肺细胞之间的炎症基因表达和炎症介质相互作用，以及c）炎症基因反应和毒代动力学多样性反映为空间炎症基因的差异在毒素暴露的大鼠肺中的表达。本文提出的微阵列和 FISH 实验的使用代表了一种新的、具有挑战性的方法来解决与霉菌毒素诱导的炎症性肺病发病有关的基本概念性问题。这项工作将增进我们对接触霉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，并促进学生特别是在真菌学、免疫毒理学、实验设计和显微镜方面的培训。