Atopic diseases, such as asthma, atopic dermatitis (AD), and inflammatory bowel disease (IBD), are among the most common chronic childhood illnesses and a frequent cause of pediatric hospitalization. These diseases are characterized by inflammation at sites of antigen exposure, namely the lung, skin and gastrointestinal (Gl) tract. The inflammation is characterized by the presence of elevated serum IgE, eosinophilia, and T cells that produce high levels of T helper type 2 (Th2) type cytokines. While there is a strong genetic component to atopic disease, contributing genetic factors are largely unknown. Our preliminary data indicate that Nedd4-family interacting protein-1 (Ndfipl) regulates atopic inflammation in mice, and may also play a role in atopic diseases in man. For example, we have shown that mice lacking Ndfipl develop a severe inflammatory disease in the skin, gut, and lung that recapitulates the phenotype of AD, IBD, and asthma in humans. Furthermore, we have identified polymorphisms that are more common in patients with asthma, AD, and IBD within the locus that encodes Ndfipl. In an attempt to understand why Ndfipl-/- T cells are hyperresponsive, we have focused our efforts on regulatory T (Treg) cell responses. Tregs are a specialized subset of T cells that suppress the response of conventional T cells. Thus, Tregs play a key role in the maintenance of tolerance to self-antigens as well as environmental allergens. The studies proposed here will test the hypothesis that Ndfipl regulates Treg development and/or function at the sites of antigen exposure. To accomplish this we will determine;1) Whether naturally-occurring thymus- derived Tregs (nTregs) are defective in Ndfipl deficient mice, 2) Whether T cells lacking Ndfipl are defective at converting into Tregs (induced Tregs), 3) Whether the inflammatory cytokines produced in Ndfipl-/- mice prevent de novo Treg conversion at sites of allergen exposure. These studies will help us to define cell types and pathways regulated by Ndfipl and advance our understanding of how Ndfipl regulates atopic disease. Our long-term goal is to therapeutically target Ndfipl pathways to treat patients with atopic diseases. The studies proposed here will help us towards this goal. In lay terms, our proposed studies will help us to understand the function of a protein, Ndfipl, that regulates atopic disease in mice and man. Specifically, we will characterize the role of Ndfipl in a subset of T cells called regulatory T cells, aptly named because of their capacity to "regulate" immune function. These studies are aimed at understanding how regulatory T cells contribute to atopic disease in mice lacking Ndfipl and have broad implications for the pathogenesis and treatment of asthma, atopic dermatitis, and inflammatory disease.
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