Migration of leukocytes to skin is directed by adhesive interactions between vascular endothelial selectins and leukocyte selectin ligands. Leukocyte selectin ligands activity is conferred by specialized carbohydrate structures displayed on leukocyte cell surface proteins. These specialized carbohydrates, including the enzymes that biosynthesize them, are expressed on distinct subsets of leukocytes and impart the capacity of leukocytes to enter skin. Thus, controlling the migration of skin-homing leukocytes associated with skin disorders, such as allergic dermatitis and psoriasis, or preventing the progression of cutaneous leukemias with selecting ligand-modifying agents represents an attractive, yet novel, therapeutic strategy. Preliminary evidence has shown that fluorinated sugars analogs of naturally-occurring sugars, principally 4-F-GlcNAc, modulate the structure and function of selectin ligands on human skin-homing leukocytes. Furthermore, 4-F-GlNAc treatment abrogates the capacity of murine skin-homing T helper 1 cells to bind to endothelial selectins, a process required for the elicitation of allergic-dependent cutaneous information. The objectives of studies outlined in this proposal are to evaluate the in vivo efficacy of 4-F- GlcNAc on cutaneous inflammation and the progression of cutaneous lymphoproliferative diseases.
We aim to establish a dose of 4-F-GlcNAc that inhibits dermal leukocyte tropism, while neither affecting leukocyte proliferation nor leukocyte adhesion molecule function involved in other leukocyte migration patterns. Analysis of anti-inflammatory and anti- tumor effects of 4-F-GlcNAc will be performed utilizing mouse models of cutaneous inflammation and lymphoproliferative diseases. The overall goals of this preclinical evaluation 4-F-GlcNAc are to demonstrate its utility as a glycobiological tool for analyzing carbohydrate structure and function and to determine its therapeutic value against leukocyte- associated skin pathologies in treatment settings that require long-term administration with minimal side effects.
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