An impermeable epithelial barrier provides a critical first line of defense for organs that interface extensively with the environment, including the ski, lung, and gut. There is growing evidence that loss of epithelial barrier integrity facilitates allergen penetration, local sensitization and, ultimately, persistence of allergic disease. Elucidation of early changes in epithelial barrier structure/function (i.e. changes that precede or coincide with sensitization) may uncover new therapeutic targets and provide alternative therapies to those currently directed toward suppressing inflammation. In this application, we provide evidence for a novel protective pathway, centered on the lipid transfer protein Stard7, which promotes barrier formation and suppresses inflammation. The results of our preliminary studies indicate that expression of Stard7 is downregulated in patients with asthma and in a mouse model of atopic dermatitis. We have disrupted the Stard7 locus in mice and show that haploinsufficiency for Stard7 (i.e. in Stard7+/- mice) leads to spontaneous dermatitis, loss of tolerance in gut epithelia and exaggerated experimental asthma. This application focuses to identification of the molecular mechanisms underlying the protective effect of Stard7 in allergic lung disease. Preliminary analyses of Stard7+/- mice suggest that (1) the protective effect of Stard7 is associated with expression in both epithelial cells and dendritic cells (DCs), (2) Stard7 is detected in nuclei of epithelial cells and DCs and (3) Stard7 associates with nuclear transcriptional complexes that include PPAR. These key findings lead to the central hypothesis that Stard7 is a novel nuclear co-factor that promotes expression of genes involved in epithelial barrier function and suppresses expression of genes involved in activation of DCs.
Three specific aims are proposed to test this hypothesis in lung tissues of WT mice and gene-targeted mice in which Stard7 expression is selectively deleted in respiratory epithelial cells (Stard7epi-/) or DCs (Stard7DC-/-).
Specific aim 1 will determine if Stard7 is required for epithelial barrier function.
Specific aim 2 will determine if Stard7 is a nuclear co-activator of epithelial barrier gne expression.
Specific aim 3 will determine if Stard7 is a modulator of DC activation. Collectively these studies will provide important, new insight into this protective pathway by identifying cells signaling pathway(s) and target genes that mediate the cell-specific barrier-enhancing and anti-inflammatory actions of Stard7.
As much as 20% of the world's population is affected by allergic disease. Despite substantial advances in understanding the pathophysiology of allergic asthma, the initial cellular and molecular events that cause susceptible individuals to acquire allergic disease are not well understood. This application presents evidence that the protein Stard7 is an important component of a novel protective pathway that is suppressed in allergic disease. The long-term goals of this study are to determine if restoration of Stard7 expression in asthmatic individuals will ameliorate the course of allergic disease.