Asthma is one of the most common chronic diseases in developed countries affecting more than 150 million individuals worldwide. It is an episodic airway disease characterized by chronic airway inflammation, mucus hypersecretion, reversible airway obstruction, and airway hyperresponsiveness (AHR). The two main causes of asthma include environmental allergens and underlying genetic susceptibility, each of which accounts for a 50% risk of developing the disease. A multitude of studies have focused on understanding how allergen-induced airway inflammation impacts the asthmatic phenotype. However, very little is known about the underlying genes contributing to the development of asthma and AHR. The genetic complexity of human asthma hinders the identification of potential genes responsible for the disease. Therefore, murine models with less genetic heterogeneity can be employed. The goal of the present study is to investigate the genes responsible for naive AHR in hyperresponsive mouse strains. The following specific aims are therefore proposed.
Specific Aim 1 : To determine the genetic loci that underlie the naive AHR phenotype of AKR/J x C57BL/6J N2 mice by quantitative trait linkage (QTL) analysis. The AHR phenotype of these mice will be determined by an invasive measure of airway resistance after aerosolized methacholine exposure. DNA will be extracted after phenotypic analysis, and a QTL analysis will be performed to determine loci associated with AHR.
Specific aim 2 : To determine the gene networks and pathways underlying the naive AHR phenotype of AKR/J x C57BL/6J and A/J x C57BL/6J N2 mice by expression QTL (eQTL) analysis. RNA from lungs will be analyzed using expression arrays and subsequent gene co-expression networks examined to determine gene pathways associated with naive AHR.
Specific aim 3 : To determine the genes on chromosomes 2 and 6 that confer the naive AHR seen in A/J mice. Hyperresponsive chromosome substitution strains (CSS) containing A/J chromosomes 2 and 6 on a C57BL/6J background will be crossed back to C57BL/6J mice to further narrow the loci associated with AHR. The AHR phenotype of subrecombinant progenies will be evaluated and genes associated with naive AHR will be identified by positional cloning. Completion of this study will further our understanding of the genetic pathophysiology of asthma which can lead to better management and treatment of the disease.
| Cozzi, Emily; Ackerman, Kate G; Lundequist, Anders et al. (2011) The naive airway hyperresponsiveness of the A/J mouse is Kit-mediated. Proc Natl Acad Sci U S A 108:12787-92 |
