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

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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.