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: 2008
• 资助国家: 加拿大
• 起止时间: 2008-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=390728
• 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，来自居民住房中常见的真菌物种的毒素引起了小鼠肺中不同毒性的毒性动物学反应。为什么不同的霉菌毒素暴露会刺激肺部这些多种炎症反应。拟议的工作是一项多学科的真菌学研究，旨在解决基本的，概念性的问题，这些问题涉及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开始。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，并帮助我们理解由真菌毒素暴露引起的肺部疾病发作。它还旨在满足我的长期目标，以更好地了解暴露于有毒真菌孢子的肺组织和细胞的某些变化以及与人类暴露有关的一些呼吸道症状的基础。提出了一系列实验性假设驱动的研究，以确定炎症反应结果中这些差异的基础机制。本研究使用细胞和/或体内大鼠模型，建议确定a）炎症性肺反应的多样性是否因潮湿建筑与毒素相关的真菌而导致的毒素是否表现出敏感性和/或炎症性介体差异的表现。 b）毒素暴露在暴露于毒素的原发性大鼠肺细胞中，毒素暴露会以毒素特异性的方式在肺细胞之间扰动炎症基因表达和炎症介质的相互作用，c）c）炎症基因反应和毒性的多样性反映为毒素炎症基因表达的差异暴露的大鼠肺。本文提出的微阵列和鱼类实验的使用代表了一种解决基本的，概念性问题的新方法，涉及霉菌毒素引起的炎症性肺部疾病发作。这项工作将提高我们对肺部疾病所产生的分子机制的理解并提供新的见解，并促进学生培训，尤其是在真菌学，免疫毒性学，实验设计和显微镜方面。