Atopic dermatitis is a highly puritic, chronic inflammatory skin disorder effecting 10-20% of children worldwide. The disease results from interaction between susceptibility genes and the host environment, but the genetic basis for the disease is not known. The overall goal of this proposal will be determine genetic loci that regulate chronic inflammation that is induced by oxazolone in a mouse model which has been propo. We propose to apply quantitative trait analysis to identify quantitative trait loci (QTL). This is made feasible by three key resources including the development and application of the BXD recombinant inbred (RI) strains of mice established at UAB. Additional resources are the statistical genetics group at UAB, that will enable analysis of single locus effect as well as interactions of QTLs and candidate genes to generate a composite of molecular pathway that influences development of atopic dermatitis. The UAB Skin Diseases Research Center will provide for the development of a Skin Proteomics Cores that facilitate immune and protein analysis. BXD recombinant inbred (RI) strains of mice can be used to dissect genetic loci associated with response. Much attention has been focused on a Th-2 response in interactions between Langerhans cells and T cells which leads to increased eosinophils, IgE and mass cells, although the genetic loci that predispose to such interactions have not been determined. We hypothesize that these processes are orchestrated by several genetic loci that regulate the initial Langerhans celI-T cell interactions, and these can be determined using QTL analysis.
Aim 1 will determine quantitative traits and associated traits associated with the inflammatory responses that occur in response to chronic exposure of the skin to oxazolone.
Aim 2 will determine QTLs that underlie ear swelling and cytokine production in the oxazalone induced chronic atopic dermatitis model.
Aim 3 will determine protein differences in the high and low atopic dermatitis BXD RI strains and select among the potential candidate genes within the given QTL. These studies should provide novel genes and proteins related to cutaneous inflammation and Th2 cytokine regulation that can be examined further in future studies.
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