A novel ubiquitin-ligase complex that prevents skin inflammation

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DESCRIPTION (provided by applicant): Project Summary/Abstract: Atopic dermatitis is a debilitating skin disease that affects 10-20% of children and 1-3% of adults worldwide. Disease severity is the result of a complex interplay between genetic and environmental factors. Yet, in spite of such high incidence, little is known about underlying genetic causes. We have identified a gene that may prevent the development of atopic dermatitis. This gene encodes a protein known as Ndfip1. Our studies have shown that Ndfip1-/- mice exhibit a Th2-mediated atopic dermatitis-like disease and die prematurely. Importantly, the gene encoding Ndfip1 is found on human chromosome 5 within a locus of susceptibility for atopic dermatitis. We recently showed that Ndfip1 regulates Itch, a member of the Nedd4-family of E3 ubiquitin ligases. In mice lacking Ndfip1, Itch does not ubiquitinate Jun proteins and thus levels of these proteins accumulate and promote Th2 cytokine production. While we have shown that Ndfip1 is required for Itch to function, we believe that Ndfip1 also regulates other E3 ligases of the Nedd4-family. Based on these data, we hypothesize that Ndfip1 prevents atopic skin disease by promoting the function of multiple Nedd4-family E3 ubiquitin ligases in T cells as well as in other cell types. In this study we will identify cell types and pathways regulated by Ndfip1. These studies will help us understand how Ndfip1 functions and lay the foundation for future studies in which we will target Ndfip1 therapeutically to treat patients with atopic dermatitis. To accomplish this, we propose the following aims: Aim 1) Our preliminary data suggest that Ndfip1-/- T cells are necessary for the development of skin disease but do not rule out that other cells facilitate disease progression. We hypothesize that defective Ndfip1-/- skin cells promote the atopic dermatitis-like disease in Ndfip1-/- mice. In this aim we will determine whether the skin disease in Ndfip1-/- mice is due solely to defective lymphocytes, or whether defects in skin cells also contribute. Aim 2) We hypothesize that T cells lacking Ndfip1 have defects in pathways that impact T cell activation. To test this, we will first determine whether T cell receptor-specificity is important. Then, we will test T cell activation by limiting T cell receptor signaling or by blocking co-stimulatory signals. These studies will reveal pathways regulated by Ndfip1. Aim 3) Regulatory T cells (Tregs) are a specialized subset of T cells that suppress activation of conventional CD4+ T cells. We hypothesize that Ndfip1 might be required for conventional T cells to respond to inhibitory signals generated by Tregs. To test this we will first determine whether Ndfip1-/- mice contain Tregs and test whether these Tregs are functional. We will then test whether T cells lacking Ndfip1 respond to inhibition by wild type T regulatory cells. PUBLIC HEALTH RELEVANCE: Project Narrative: Atopic dermatitis is a debilitating skin disease caused by genetic and environmental factors. We have identified a gene, known as Ndfip1 that may prevent the development of atopic dermatitis. In this study we will identify cell types and pathways regulated by Ndfip1. These studies will lay the foundation for future studies in which we will target Ndfip1 therapeutically to treat patients with atopic dermatitis or other inflammatory skin conditions.