The ability to regulate and control the immune response has significant implications in areas like musculoskeletal and skin diseases, allergies, organ transplant and cancer. AA is an autoimmune disease of the hair follicle that causes loss of hair and is found in 2% of the population. The membrane- translocating sequence (MTS), which is a 12-aminoacid residue (AAVLLPVLLAAP) sequence with a function as a cellular import signal. In previous work we show that MTS sequence could efficiently deliver a large variety of proteins as fusion proteins, while also maintaining the function of the protein. In preliminary experiments to determine localization of the fusion protein we created a fusion protein, that contains a dominant negative form of the NF-kappaB inhibitor IkappaB-alpha(deltaN) . It was possible to visualize the protein in the cytoplasm of cell. These finding suggested that the IkappaB-alpha(deltaN)-MTS fusion protein can be delivered efficiently into other cell types, such a T lymphocytes where it will be function as an inhibitor of Rel/NF-kappaB translocation and block the NF-kappaB cascade. In this project we propose to test this the potential function of MTS protein in modification of an autoimmune disease hypothesis in the autoimmune skin disease, alopecia areata(AA) with the long-term prospect of intervening in other important skin disorders such psoriasis and graft vs host disease. To test this hypothesis, I propose the following specific aims: -Verify the function IkappaB-alpha(deltaN)-MTS fusion protein in vitro using Jurkat T cells, to show that this protein blocks Rel/NF-kappaB nuclear translocation following T cell activation. - Determine if IkappaB(deltaN)-MTS alters the course of an autoimmune disease using the animal model of AA. To characterize the histologic changes in cellular composition of skin lesions induced by IkappaB- alpha(deltaN) MTS and to use mice that express a reporter for NF-kappaB activation as a transgene.
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