The long term objectives of this project are to identify novel genes associated with the pathogenesis of atopic asthma, which have escaped detection employing current expression profiling techniques. Such genes would be prime candidates for future studies on asthma genetics, and potentially would be new drug candidates. To achieve this objective we propose to utilize a new approach which derives from the concept that individual genes do not function in isolation, but instead as members of integrated coexpression networks. We will utilize methodology which has recently been developed for analysis of genome wide microarray expression profiles, that identifies genes based on their connectivity to coordinately expressed genes, and in doing so assigns them to coexpression networks. Of particular interest are highly interconnected genes which serve as hubs to stabilize networks and/or as links between networks. An archetypal example of such hub genes is NF B which integrates signals from multiple interlinked genes and gene networks. In this project we will focus on identification of genes operative within immune response pathways associated with the induction and expression of the disease atopic asthma.
Our specific aims are: (i) to identify and characterize gene expression networks operative in Th-cell responses to aeroallergen amongst sensitized atopics;(ii) to identify network level variations in aeroallergen-driven Th-cell gene expression programs amongst sensitized atopics which are associated with expression of the clinical asthmatic phenotype;(iii) to validate these network level variations (and their constituent putative """"""""asthma candidate genes"""""""") in an independent study cohort of atopic asthmatics.Narrative This project seeks to develop a new and improved approach to the identification of disease associated genes relevant to the pathogenesis of atopic asthma. Such genes would be prime candidate drug targets. This disease remains a heavy burden on health care services internationally, and more effective drugs for treatment (and prevention) are urgently needed, and the approach to be followed in the project has the potential to develop methods that would markedly improve drug target identification.
| Custovic, Adnan; Soderstrom, Lars; Ahlstedt, Staffan et al. (2011) Allergen-specific IgG antibody levels modify the relationship between allergen-specific IgE and wheezing in childhood. J Allergy Clin Immunol 127:1480-5 |
| Bosco, Anthony; McKenna, Kathy L; Firth, Martin J et al. (2009) A network modeling approach to analysis of the Th2 memory responses underlying human atopic disease. J Immunol 182:6011-21 |
